exploration of the clinical interaction ... - ucl...

EXPLORATION OF THE CLINICAL

INTERACTION BETWEEN VASCULAR

TARGETING AGENTS AND RADIOTHERAPY

A thesis submitted to University College London

for the degree of MD (Res)

Henry Campbell Mandeville

University College London

Marie Curie Research Wing

Mount Vernon Hospital

Rickmansworth Road

Middlesex

HA6 2RN

UK

1

This thesis is dedicated to my wife, Sugi, and my children,

Thomas and Sarasa. For their endless encouragement, patience,

understanding and laughter, throughout my experiments and write

up.

2

Declaration

I, Henry Campbell Mandeville confirm that the work presented in this thesis is

my own. Where information has been derived from other sources, I confirm

that this has been indicated in the thesis.

Signed Date

3

Abstract

Preclinical studies of vascular disruptive and anti-angiogenic agents, combined with

radiation, have demonstrated the potential for enhanced anti-tumour activity.

However, the optimal strategy and scheduling for combining these treatments with

radiotherapy remains uncertain. In this thesis, combretastatin-A4-phosphate (CA4P)

given concurrently with fractionated radiotherapy has been studied using preclinical

models, in addition to assessing the impacts of adding the nitric oxide synthase

inhibitor, N(omega)-nitro-L-arginine (L-NNA), or the anti-EGFR monoclonal antibody,

cetuximab, to this combination. As part of an ongoing phase Ib clinical trial, the

combination of CA4P and radiotherapy was investigated in patients with non-small

cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC),

where concurrent cetuximab was also given.

Functional imaging techniques, such as dynamic contrast enhanced (DCE)-CT and

positron emission tomography (PET), provide non-invasive biomarkers, which can

be harnessed to aid diagnosis, determine response to treatment and also offer

prognostic information. The use of volumetric DCE-CT parameters as biomarkers of

tumour hypoxia and angiogenesis in NSCLC has been explored here, with

significant negative correlations demonstrated between DCE-CT parameters and

immunohistochemical staining of intra-tumoural hypoxia. This illustrates the potential

ability of volumetric DCE-CT to quantify whole tumour hypoxia in NSCLC.

The translational research described in this thesis, has established that the vascular

disruptive effects of CA4P can be safely used in combination with fractionated

radiotherapy in the clinical setting, producing demonstrable tumour vascular effects.

However, despite promising preclinical tumour growth delay effects, the addition of

cetuximab produced dose-limiting cardiotoxicity. In patients receiving CA4P and

4

radiotherapy, DCE-CT and circulatory biomarkers, including cytokines (VEGF,

VEGFR-1, G-CSF and SDF-1), were utilised to assess treatment-induced changes

in tumour vascularity and vasculogenesis. The findings in this thesis provide further

information to guide future studies combining vascular targeted therapies and

radiation, highlighting the role of DCE-CT and functional imaging in such work.

5

Acknowledgements

Professor Peter Hoskin, who provided me with the opportunity to undertake this

research and who, as my supervisor, has supported and guided me in my efforts.

Dr Vicky Goh, who supervised all of the experiments using DCE-CT and has

provided constant encouragement, advice and critical appraisal.

Dr Sally Hill, who supervised and facilitated all the laboratory work in this thesis.

Without the contributions of the following people, the work described in this thesis

would not have been possible.

Marie Curie Research Wing

Prof Michele Saunders, Dr Roberto Alonzi, Mrs Jessica Finch, Dr Quan Ng, Ms

Jackie Anderson

Paul Strickland Scanner Centre

Dr Anwar Padhani, Dr Wai-lep Wong, Dr Jane Chambers, Dr Jayne Taylor

Gray Cancer Institute

Mrs Frances Daley, Mrs Vivien Prise, Miss Gemma Lewis, Dr Paul Barber, Mr Glenn

Pierce, Dr Michael Stratford, Ms Lisa Folkes

University of Sheffield

Prof Gillian Tozer

Harefield Hospital

Dr Margaret Burke, Dr Alex Bell, Mr Edward Townsend

University of Hertfordshire

Mr Robert Kozarski

University of Oxford/ NHSBT Oxford

Prof Adrian Harris, Dr Jon Smythe, Ms Nita Fisher, Dr Lisa McRae

6

In addition to the experiments and analysis undertaken by myself, other individuals

have assisted in the work presented in this thesis. Dr Michael Stratford and Ms Lisa

Folkes performed the preclinical pharmacokinetic specimen analysis presented in

Chapters 3 and 4. Mrs Frances Daley taught me the principles for the

immunohistochemical staining, assisting me in performing this and also performing

the majority of the staining presented in Chapter 5. Dr Quan Ng performed the DCE-

CT and FDG-PET image analysis and Dr Robert Kozarkski assisted in the statistical

analysis, presented in Chapter 5. Finally, Dr Jon Smythe, Ms Nita Fisher and Dr Lisa

McRae performed the cytokine testing presented in Chapter 7 at NHSBT in Oxford.

7

Table of Contents Chapter 1 Introduction 21

1.1 Targeting tumour vasculature to enhance the efficacy of radiotherapy

21

1.2 Tumour microenvironment 23 1.2.1 Tumour vascular architecture and function 23 1.2.2 Angiogenesis 25 1.2.3 Metabolic microenvironment 28

1.3 Therapeutic targeting of tumour vasculature 30 1.3.1 Vascular disruption 30 1.3.2 Small molecule vascular disruptive agents 30 1.3.2.1 Tubulin-binding agents 30 1.3.2.2 Combretastatin A4 phosphate (CA4P) 31 1.3.2.3 Other tubulin-binding vascular disruptive agents 36 1.3.2.4 Flavonoid vascular disruptive agents 38 1.3.2.5 Ligand directed vascular disruptive agents 40 1.3.3 Anti-angiogenesis 41 1.3.3.1 Indirect and mixed angiogenesis inhibition 42 1.3.3.2 Direct angiogenesis inhibition 45 1.3.3.3 Combined anti-angiogenesis and vascular disruption 46 1.3.4 Nitric oxide and vascular function 47 1.3.4.1 Vascular effects of NOS inhibition 47 1.3.4.2 Combined NOS inhibition and other vascular directed

therapies 49

1.3.5 Vascular effects of conventional anti-cancer therapies 51 1.3.5.1 Radiotherapy 51 1.3.5.2 Chemotherapy and hormonal therapy 52

1.4 Combining radiotherapy and vascular directed therapy 53 1.4.1 Vascular disruptive agents and radiotherapy 54 1.4.1.1 Combretastatin A4 phosphate and radiotherapy 56 1.4.1.2 Other combretastatins and radiotherapy 59 1.4.1.3 Other tubulin-binding VDAs and radiotherapy 60 1.4.1.4 Flavonoid VDAs and radiotherapy 61 1.4.2 Hyperthermia in combination with VDAs and radiotherapy 63 1.4.3 Bioreductive cytotoxics in combination with VDAs and

radiotherapy 64

1.4.4 Dual targeting of tumour vasculature in combination with radiotherapy

65

1.4.4.1 Anti-angiogenesis 65 1.4.4.2 EGFR inhibition 67 1.4.4.3 NOS inhibition 68

1.5 Functional imaging 69 1.5.1 The role of functional imaging in assessing response to

vascular directed therapies 69

1.5.2 Dynamic contrast enhanced CT 70 1.5.3 Other functional imaging techniques 74 1.5.3.1 Dynamic contrast enhanced MRI 74

8

1.5.3.2 PET 77 1.5.3.3 Ultrasound 78 1.6 Laboratory techniques for the assessment of tumour

vasculature and response 80

1.6.1 Immunohistochemical quantification of tumour vascularity 80 1.6.2 Quantification of tumour angiogenesis by circulatory

biomarkers 83

1.6.3 Immunohistochemical quantification of tumour hypoxia 84

1.7 Aims 88

Chapter 2 Material and Methods 92

2.1 Preclinical Studies 92 2.1.1 Tumours 92 2.1.1.1 CaNT 92 2.1.1.2 FaDu 92 2.1.2 Drug Treatments 93 2.1.2.1 Combretastatin A4 Phosphate (CA4P) 93 2.1.2.1 N(omega)-nitro-L-arginine (L-NNA) 93 2.1.2.3 Cetuximab (C225) 93 2.1.3 Tumour Irradiation 93 2.1.3.1 Local tumour irradiation 94 2.1.3.2 Whole body irradiation 94 2.1.4 Tumour Growth Delay 94 2.1.5 Pharmacokinetic studies 95 2.1.5.1 L-NNA 95 2.1.5.2 CA4P 96

2.2 Clinical treatments 97 2.2.1 Radiotherapy 97 2.2.1.1 High dose palliative lung radiotherapy 97 2.2.1.2 Radical head and neck radiotherapy 97 2.2.2 Concurrent CA4P 98 2.2.3 Concurrent Cetuximab 99 2.2.4 Pimonidazole 99

2.3 Imaging Techniques 1002.3.1 DCE-CT 1002.3.1.1 Volumetric Technique 1002.3.1.2 Single level technique 1032.3.1.3 DCE-CT Reproducibility 1042.3.2 FDG-PET/ CT 105

2.4 ELISA 106

2.5 Immunohistochemistry 1082.5.1 Human lung specimens 1082.5.2 Materials 1092.5.3 Preparation of solutions and reagents 1092.5.3.1 0.5M Tris buffer saline (TBS) 1092.5.3.2 Zinc Fixative 1092.5.4 Preparation of histological slides for staining 110

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2.5.5 Antigen retrieval 1102.5.5.1 Pretreatment with 0.1% Chymotrypsin 1102.5.5.2 Heat induced epitope retrieval (HIER) 1112.5.6 Immunohistochemical staining 1112.5.6.1 CD34 1112.5.6.2 Pimonidazole 1122.5.6.3 Glut-1 1122.5.6.4 Completion of staining and slide preparation 1122.5.7 Digitisation of histology slides 1132.5.8 Quantification of immunohistochemical staining 114

2.6 Statistical Analysis 1162.6.1 Tumour Growth Delay 1162.6.2 Lymph node metastases 1162.6.3 Immunohistochemical, DCE-CT and FDG-PET derived

parameters 116

2.6.4 Blood count and cytokine parameters 117 Chapter 3 Preclinical evaluation of nitric oxide synthase

inhibition alone or in combination with radiation and vascular disruption

122

3.1 Aims 122

3.2 Introduction 123

3.3 Methods 1243.3.1 Tumours and Treatments 1243.3.2 Pharmacokinetics 1243.3.3 Tumour Growth Delay Treatment Groups 1243.3.4 Statistical analysis 126

3.4 Results 1263.4.1 Pharmacokinetic studies 1263.4.2 Tumour Growth Delay Studies 1273.4.2.1 Single agent L-NNA schedules 1273.4.2.2 Combined L-NNA and CA4P 1283.4.2.3 Combined L-NNA, CA4P and Radiotherapy 128

3.5 Discussion 129

3.6 Conclusion 132 Chapter 4 Preclinical evaluation of EGFR inhibition in

combination with radiation and CA4P 143

4.1 Aims 143


4.3 Methods 1454.3.1 Tumours and Treatments 1454.3.2 Treatment Groups 1454.3.3 Pharmacokinetics 1454.3.4 Statistical analysis 146

4.4 Results 1464.4.1 Tumour Growth Delay Studies 146

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4.4.1.1 CA4P and cetuximab 1464.4.1.2 CA4P, cetuximab and radiotherapy 1464.4.1.3 Lymph node metastases 1494.4.2 Pharmacokinetic studies 151

4.5 Discussion 152

4.6 Conclusion 155

Chapter 5 Pathophysiological correlates of volumetric DCE-CT

in resected lung cancers 163

5.1 Aims 163


5.3 Methods 1655.3.1 Patients and Treatments 1655.3.2 Treatment Group 1665.3.3 Volumetric DCE-CT 1665.3.4 Histology 1665.3.5 Statistical analysis 167

5.4 Results 1675.4.1 Patient and tumour characteristics 1675.4.2 Tumour blood volume, vascularity and hypoxia 1685.4.3 Tumour permeability surface area product, vascularity and

hypoxia 168

5.4.4 Tumour blood flow, vascularity and hypoxia 1695.4.5 Tumour maximum standard uptake value, vascularity and

hypoxia 169

5.4.6 Tumour DCE-CT and PET parameters 1695.4.7 Qualitative and quantitative analysis of immunohistochemistry 1705.4.8 Immunohistochemical assessment of tumour vascularity and

hypoxia 170

5.4.9 Fraction and intensity of immunohistochemical stain 171

5.5 Discussion 171

5.6 Conclusion 179 Chapter 6 Tumour vascular effects of combined vascular

disruption and radiation in advanced NSCLC 196

6.1 Aims 196


6.3 Methods 1976.3.1 Patient selection and recruitment 1976.3.2 Imaging 1996.3.3 Statistical analysis 199

6.4 Results 1996.4.1 Lung Volumetric DCE- CT 1996.4.2 Reproducibility 2006.4.3 Blood Volume 2016.4.4 Permeability surface area product 202

11

6.5 Discussion 204

6.6 Conclusion 208

Chapter 7 Tumour vascular effects of combined vascular

disruption and radiation in advanced NSCLC 223

7.1 Aims 223


7.3 Methods 2257.3.1 Patient selection and recruitment 2257.3.2 Imaging 2257.3.3 Blood sampling 2267.3.4 Statistical analysis 226

7.4 Results 2267.4.1 Head and Neck Single Level DCE- CT 2267.4.2 Blood Volume 2287.4.3 Permeability surface area product 2287.4.4 Blood Flow 2307.4.5 Blood Testing 2317.4.6 Full Blood Count 2317.4.7 ELISA 232

7.5 Discussion 234

7.6 Conclusion 238 Chapter 8 Concluding discussion 260

Appendix A Matching of histology with Dynamic Contrast

Enhanced CT 270

Appendix B UKR-104 study inclusion and exclusion criteria 272

References 275

12

List of Tables 1.1 Pro- and Anti-angiogenic Factors 89

1.2 Advantages and disadvantages of combining VDAs and radiotherapy 90

1.3 Different functional imaging techniques for the assessment of tumour vasculature

91

2.1 Phase Ib Trial of CA4P (Combretastatin A-4 Phosphate) in

Combination with Radiotherapy in Patients with Advanced Cancer of the Lung, Head & Neck or Prostate, CA4P Protocol: UKR-104

118

2.2 Key materials used for immunohistochemical staining 121

3.1 Combinations of treatments studied 134

4.1 Time (days) to development of lymph node metastases, or end of

experiment for those not developing lymph node metastases 156

5.1 Staging and histopathological features of 14 resected NSCLC tumours 181

5.2 Spearman rank correlations of mean DCE-CT derived blood volume (BV), permeability surface area product (PS), blood flow (BF) and maximum standard uptake value (SUVmax) with the fraction stained for 3 different immunohistochemical stains

186

5.3 Spearman rank correlations between the mean DCE-CT derived parameters of blood flow (BF), blood volume (BV) and permeability surface area product (PS), and for each of these with maximum standard uptake value (SUVmax)

189

5.4 Mean (standard deviation) DCE-CT and FDG-PET parameters according to the pathological features of resected NSCLC tumours

190

5.5 Spearman rank correlations between 3 different immunohistochemical stains

193

5.6 Spearman rank correlations between the fraction stained, average intensity and total intensity for the 3 different immunohistochemical stains

195

6.1 Reproducibility and repeatability statistics from paired studies

performed on 24 patients, with NSCLC due to receive high dose palliative radiotherapy, measuring whole tumour permeability surface area product (PS) and blood volume (BV)

210

6.2 DCE-CT derived median blood volume (BV) values (ml/100ml) and percentage change from mean baseline for NSCLC patients receiving twice weekly CA4P and RT (UKR104 cohort 7)

212

6.3 DCE-CT derived median blood volume (BV) values (ml/100ml) and percentage change from previous time point for NSCLC patients receiving twice weekly CA4P and RT (UKR104 cohort 7)

213

13

6.4 DCE-CT derived median blood volume (BV) values (ml/100ml) and percentage change from mean baseline for NSCLC patients receiving single dose and weekly CA4P and RT (UKR104 cohorts1+2)

215

6.5 DCE-CT derived median blood volume (BV) values (ml/100ml) and percentage change from previous time point for NSCLC patients receiving single dose and weekly CA4P and RT (UKR104 cohorts1+2)

216

6.6 DCE-CT derived permeability surface area product (PS) values (ml/100ml/min) and percentage change from mean baseline for NSCLC patients receiving twice weekly CA4P and RT (UKR104 cohort 7)

218

6.7 DCE-CT derived permeability surface area product (PS) values (ml/100ml/min) and percentage change from previous time point for NSCLC patients receiving twice weekly CA4P and RT (UKR104 cohort 7)

219

6.8 DCE-CT derived permeability surface area product (PS) values (ml/100ml/min) and percentage change from mean baseline for NSCLC patients receiving single dose and weekly CA4P and RT (UKR104 cohorts1+2)

221

6.9 DCE-CT derived permeability surface area product (PS) values (ml/100ml/min) and percentage change from previous time point for NSCLC patients receiving single dose and weekly CA4P and RT (UKR104 cohorts1+2)

222

7.1 DCE-CT derived median blood volume (BV) values (ml/100ml),

median permeability surface area product (PS) values (ml/100ml/min) and median Blood Flow (BF) values (ml/100ml/min), plus percentage change from previous time point, for each patient and group mean (UKR104 cohort 6)

240

7.2 DCE-CT derived median blood volume (BV) values (ml/100ml) and percentage change from mean baseline for patients with SCC Head & Neck receiving weekly CA4P, cetuximab and RT (UKR104 cohort 6)

242

7.3 DCE-CT derived median blood volume (BV) values (ml/100ml) and percentage change from previous time point for patients with SCC Head & Neck receiving weekly CA4P, cetuximab and RT (UKR104 cohort 6)

243

7.4 DCE-CT derived median permeability surface area product (PS) values (ml/100ml/min) and percentage change from mean baseline for patients with SCC Head & Neck receiving weekly CA4P, cetuximab and RT (UKR104 cohort 6)

245

7.5 DCE-CT derived median permeability surface area product (PS) values (ml/100ml/min) and percentage change from previous time point for patients with SCC Head & Neck receiving weekly CA4P, cetuximab and RT (UKR104 cohort 6)

246

7.6 DCE-CT derived median Blood Flow (BF) values (ml/100ml/min) and percentage change from mean baseline for patients with SCC Head & Neck receiving weekly CA4P, cetuximab and RT (UKR104 cohort 6)

248

7.7 DCE-CT derived median Blood Flow (BF) values (ml/100ml/min) and percentage change from previous time point for patients with SCC Head & Neck receiving weekly CA4P, cetuximab and RT (UKR104 cohort 6)

249

14

7.8 Full blood count results for head and neck cancer patients receiving CA4P, cetuximab and radical radiotherapy (UKR104 cohort 6)

254

7.9 ELISA results for head and neck cancer patients receiving CA4P, cetuximab and radical radiotherapy (UKR104 cohort 6)

259

15

List of Figures 2.1 Colour parametric maps of permeability surface area product (PS),

from a patient with NSCLC 119

2.2 Parametric images of blood volume (BV) in a patient with HNSCC 120 3.1 Plasma and tissue concentrations of L-NNA in CBA female mice after

single or five daily doses of 10 mg/kg i.p 135

3.2 Plasma and tissue concentrations of continuous oral L-NNA (1 mg/ml drinking water) in female CBA mice

136

3.3 Effect of different L-NNA schedules when administered as a single agent or weekly CA4P on the growth of CaNT murine tumours

137

3.4 Effect of weekly CA4P combined with different L-NNA schedules on the growth of CaNT murine tumours

138

3.5 Effect of daily CA4P in combination with oral L-NNA schedule on the growth of CaNT murine tumours

139

3.6 Effect of different L-NNA schedules on the growth of CaNT murine tumours in combination with fractionated radiotherapy

140

3.7 Effect of oral L-NNA schedule on the growth of CaNT murine tumours in combination with fractionated radiotherapy and weekly CA4P

141

3.8 Effect of oral L-NNA schedule on the growth of CaNT murine tumours in combination with fractionated radiotherapy and daily CA4P

142

4.1 Effect of CA4P 100mg/kg i.p. weekly or cetuximab (Cet) 1mg i.p. every

3 days for 4 doses on growth of FaDu tumours when administered as single agents or in combination

157

4.2 Effect of fractionated radiotherapy 16 Gray in 8 fractions (2 Gray per fraction), 4 fractions per week with a 3 day treatment gap on growth of FaDu tumours when administered either alone, plus CA4P 100mg/kg i.p. weekly or cetuximab (Cet) 1mg i.p. every 3 days for 4 doses or in combination with both CA4P and cetuximab

158

4.3 Effect of fractionated radiotherapy 20 Gray in 8 fractions (2.5 Gray per fraction), 4 fractions per week with a 3 day treatment gap on growth of FaDu tumours when administered either alone, plus CA4P 100mg/kg i.p. weekly or cetuximab (Cet) 1mg i.p. every 3 days for 4 doses or in combination with both CA4P and cetuximab

159

4.4 Effect of fractionated radiotherapy 24 Gray in 8 fractions (3 Gray per fraction), 4 fractions per week with a 3 day treatment gap on growth of FaDu tumours when administered either alone, plus CA4P 100mg/kg i.p. weekly or cetuximab (Cet) 1mg i.p. every 3 days for 4 doses or in combination with both CA4P and cetuximab

160

4.5 Plasma combretastatin A4 and combretastatin A4 phosphate concentrations following CA4P 100mg/kg ip +/- cetuximab (Cet) 1mg i.p. every 3 days for 2 doses

161

16

4.6 Tumour combretastatin A4 and combretastatin A4 phosphate concentrations following CA4P 100mg/kg i.p. +/- cetuximab (Cet) 1mg ip every 3 days for 2 doses

162

5.1 Correlation of mean DCE-CT derived blood volume (BV) with the

fraction stained for 3 different immunohistochemical stains 182

5.2 Correlation of mean DCE-CT derived permeability surface area product (PS) with the fraction stained for 3 different immunohistochemical stains

183

5.3 Correlation of mean DCE-CT derived blood flow (BF) with the fraction stained for 3 different immunohistochemical stains

184

5.4 Correlation of maximum standard uptake value (SUVmax) with the fraction stained for 3 different immunohistochemical stains

185

5.5 Correlation between the mean DCE-CT derived parameters 1875.6 Correlation between maximum standard uptake value (SUVmax) and

the mean DCE-CT derived parameters 188

5.7 Digital microscope images of immunohistochemical stained whole tumour sections from resected NSCLCs, showing the staining intensity for (i) Pimonidazole and (ii) Glut-1, in different tumour subtypes

191

5.8 Correlation between 3 different immunohistochemical stains 1925.9 Correlation between the fraction stained, average intensity and total

intensity for the 3 different immunohistochemical stains 194

6.1 Colour parametric maps of DCE-CT derived whole tumour blood

volume (BV) for patient BS37 209

6.2 Graph of median whole tumour blood volume for NSCLC patients receiving twice weekly CA4P and RT (Cohort 7)

211

6.3 Graph of median whole tumour blood volume for NSCLC patients receiving single dose or weekly CA4P and RT (Cohorts 1 + 2)

214

6.4 Graph of median whole tumour permeability surface area product for NSCLC patients receiving twice weekly CA4P and RT (Cohort 7)

217

6.5 Graph of median whole tumour permeability surface area product for NSCLC patients receiving single or weekly CA4P and RT (Cohorts 1 + 2)

220

7.1 Colour parametric maps of single level DCE-CT derived tumour blood

volume (BV) and blood flow (BF) for patient HC38 239

7.2 Graph of median single level tumour blood volume for HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6)

241

7.3 Graph of median single level tumour permeability surface area product for HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6)

244

7.4 Graph of median single level tumour blood flow for HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6)

247

17

7.5 Graph of individual and group mean changes in white cell count for HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6)

250

7.6 Graph of individual and group mean changes in neutrophil count for HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6)

251

7.7 Graph of individual and group mean changes in lymphocyte count for HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6)

252

7.8 Graph of individual and group mean changes in monocyte count for HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6)

253

7.9 Graph of individual and group mean changes in plasma VEGF concentration for HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6)

255

7.10 Graph of individual and group mean changes in plasma VEGFR1 concentration for HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6)

256

7.11 Graph of individual and group mean changes in plasma G-CSF concentration for HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6)

257

7.12 Graph of individual and group mean changes in plasma SDF-1 concentration for HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6)

258

A1 Specimen pictures from time of cut-up 270A2 Tissue block picture: section from middle of the tumour 270A3 Specimen picture and immunohistochemical staining for CD34,

pimonidazole (Pimo) and Glut-1, of section obtained from middle of tumour

271

18

Publications arising from this research Original research QS Ng, H Mandeville, V Goh, R Alonzi, J Milner, D Carnell, K Meer, MI Saunders,

AR Padhani, PJ Hoskin (2011). A phase Ib trial of radiotherapy in combination with

combretastatin-A4-phosphate in patients with non-small cell lung cancer, prostate

adenocarcinoma, and squamous cell carcinoma of the head and neck. Ann Oncol.

2011 Jul 15. [Epub ahead of print]

Book Chapters H.C. Mandeville and P.J. Hoskin. Vascular disruptive agents in combination with

radiotherapy. In Vascular Disruptive Agents for the Treatment of Cancer. 1st Edition,

T. Meyer (Ed.), New York: Springer, 2010. pp231- 250.

Abstracts

H. C. Mandeville, V. Goh, Q. S. Ng, J. Milner, M. I. Saunders, P. J. Hoskin.

Volumetric perfusion CT assessment of concurrent combretastatin-A4-phosphate

(CA4P) and radiotherapy (RT) in non-small cell lung cancer. J Clin Oncol 26: 2008

(May 20 suppl; abstr 14584). ASCO 2008

H.C. Mandeville, P. J. Hoskin, G. Lewis, V.E. Prise, M I Saunders, G.M. Tozer, S.A.

Hill. Nitric oxide synthase inhibition and the effects combination with combretastatin-

A4-phosphate and radiotherapy. Radiotherapy & Oncology, Vol 90 Suppl. 3 (2009),

S54, Abstract number 133. ESTRO September 2008

H. C. Mandeville, P. J. Hoskin, G. Lewis, V. E Prise, M. I. Saunders, G. M. Tozer, S.

A. Hill. N(omega)-nitro-L-arginine (L-NNA) and the effects of its combination with

combretastatin-A4-phosphate and radiotherapy. CRUK Clinical Fellows Meeting Nov

2008.

H. Mandeville, V.J. Goh, Q. Ng, J. Milner, M. Saunders, P. Hoskin. Volumetric

helical perfusion CT assessment of concurrent combretastatin-A4-phosphate and

radiotherapy in non-small cell lung cancer. ECR March 2009

19

Mandeville HC, Hill SA, Goh VJ, Milner J, Lewis G, Saunders MI, Tozer GM, Hoskin

PJ. Preclinical and clinical investigation of combretastatin-A4-phosphate induced

vascular disruption in combination with the EGFR inhibitor cetuximab and

fractionated radiotherapy in HNSCC. Radiotherapy & Oncology, Vol Suppl. 2

(2008), S156, Abstract number 471. ICTR March 2009

Q.S. Ng, H. Mandeville, W.L. Wong, J. Chambers, M.M. Burke, A. Bell, E.

Townsend, M.I. Saunders, P.J. Hoskin, V. Goh. Volumetric helical perfusion CT and

FDG-PET/CT as prognostic biomarkers in operable non-small cell lung cancer:

correlation with clinico-pathological parameters. ECCO - ESMO September 2009.

Q.S. Ng, H. Mandeville, W.L. Wong, J. Chambers, M.M. Burke, A. Bell, E.

Townsend, M.I. Saunders, P.J. Hoskin, V. Goh. Volumetric helical perfusion CT and

FDG-PET/CT as prognostic biomarkers in operable non-small cell lung cancer:

correlation with clinico-pathological parameters. RSNA December 2009.

H.C. Mandeville, V. Goh, F. Daley, P. Barber, Q.S. Ng, M. Burke, R.Kozarski, G.

Pierce, A Bell, E. Townsend, M. I. Saunders, P. J. Hoskin. Validation of volumetric

DCE-CT as a biomarker of tumour hypoxia and vascularity in NSCLC. Radiotherapy

& Oncology, Vol 96 Suppl. 1 (2010), S82, Abstract number 222. ESTRO September

2010. Selected for oral presentation in Young Scientist Poster Session.

20

CHAPTER 1

Introduction

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1.7 Aims

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! ! ! ! ! !Pro-Angiogenic Factors Anti-angiogenic Factors

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Table 1.1

]31[!'%(!<%&-['%/-1/#%-$!='$&13*9!

89

Advantages Disadvantages

Y%+'%$#(!&20123!$1%&31.!! BX<[-%(2$#(!&20123!+461P-'!

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Table 1.2

<()'%&'/#*!'%(!(-*'()'%&'/#*!1,!$10;-%-%/!BX<*!'%(!3'(-1&+#3'649!

90

!

! DCE-CT DCE-MRI PET Ultrasound

Tracer T1(-%'&#(!

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J'(1.-%-20!

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>?[Z!.';#..#(!

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Measured

Parameters

L=8!LB8!a::8!]R! `&3'%*8!5#68!)#!

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L=8!LB! L=8!LB8!a::!

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$+'..#%/-%/!

M-0-&#(!

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3#!"#/-1%'.!

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BF= blood flow, BV= blood volume, MTT= mean transit time, PS= permeability surface area

product, K&3'%*= transfer constant, k#6= rate constant, v#= extravascular-extracellular volume

for a given tissue volume

!

Table 1.3

X-,,#3#%&!,2%$&-1%'.!-0'/-%/!&#$+%-N2#*!,13!&+#!'**#**0#%&!1,!&20123!)'*$2.'&23#!

!

91

CHAPTER 2

Materials and Methods

2.1 Preclinical Studies!

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2.3 Imaging Techniques

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No.Disease/Trt.Fraction/DoseGy/day/wk

MT

WTh

FS

SM

TW

Th

FS

SM

TW

ThF

SS

MT

WT

hF

SS

MT

WTh

FS

SM

TW

ThF

SS

MT

WTh

FNSCLC

1R

adia

tion

27/6

Gy

4.5/

9R

RR

RR

RC

A4P

50 m

g/m

2C

2R

adia

tion

27/6

Gy

4.5/

9R

RR

RR

RC

A4P

50 m

g/m

2C

CC

7R

adia

tion

27/6

Gy

4.5/

9R

RR

RR

RC

A4P

50 m

g/m

2C

CC

CC

C

Prostate

3R

adia

tion

55-5

7/19

-20

Gy

2.75

/13.

75R

RR

RR

RR

RR

RR

RR

RR

RR

RR

RC

A4P

50 m

g/m

2C

4R

adia

tion

55-5

7/19

-20

Gy

2.75

/13.

75R

RR

RR

RR

RR

RR

RR

RR

RR

RR

RC

A4P

50 m

g/m

2C

CC

C

5R

adia

tion

55-5

7/19

-20

Gy

2.75

/13.

75R

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

CA

4P63

mg/

m2

CC

CC

CC

C

H&N

6R

adia

tion

64-7

0/32

-35

Gy

2/10

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RC

A4P

50 m

g/m

2C

CC

CC

CC

Cet

uxim

ab*

250

mg/

m2

CC

CC

CC

C

Wee

k 3

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ab s

houl

d be

giv

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me

day

ever

y w

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the

actu

al d

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betw

een

patie

nts

Wee

k 4

Wee

k 5

Wee

k 6

Wee

k 7

Cohorts

Wee

k 2

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k 1

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11

8

Tabl

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Figure 2.1

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Figure 2.2

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120

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Table 2.2

4,D!'$1,)&$#/!./,-!7*)!&''.%*2&/1*+2,'&+$#!/1$&%&%RF!

!

121

CHAPTER 3

Preclinical evaluation of nitric oxide synthase

inhibition alone or in combination with radiation

and vascular disruption.

!

3.1 Aims

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122

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123

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!!

3.6 Conclusion

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132

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133

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O"! @! @! @!

O"!k!C7?D!HSKKQ! 5! 5! @!

O"!k!C7?D!H<KQ! 5! 5! @!

!

Table 3.1

Combinations of treatments studied: L-NNA 2qw - 10mg/ kg ip on days 3, 4, 10, and

11; L-NNA 5qw - 10mg/ kg ip on days 0- 4 and 7- 11; L-NNA O- 1mg/ ml

continuously in drinking water; CA4P (100)- 100mg/ kg ip on days 4 and 11;

CA4P(50)- 50mg/ kg ip on days 0-4 and 7- 11; RT- radiotherapy, 40 Gray in 8 daily

fractions on days 0-3 and 7-10.!

134

!7!

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142

CHAPTER 4

Preclinical evaluation of EGFR inhibition in

combination with radiation and vascular

disruption.

!

4.1 Aims

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S*! &,)1!+#'A!%*,-*/%$!-*&)2&6(#6'!%..%/&!+-1!#01%'D%$!0%&+%%*!/%&67)(-0<!B34C!

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9'#+&,!$%8-:!/#(5-'%$! &#! '-$)-&)#*!-8#*%?!",%!-*&)2&6(#6'!%..%/&1!#.! '-$)#&,%'-5:!

5861!/%&67)(-0!)*!&,)1!&6(#6'!(#$%8!+%'%!/#*.)'(%$<!$%(#*1&'-&%$!0:!&,%!'%$6/%$!

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0%*%.)/)-8!%..%/&1!1%%*!)*!/#(0)*-&)#*!+)&,!/%&67)(-0!-*$!'-$)#&,%'-5:<!1)*98%!-9%*&!

B34C! )*! /#(0)*-&)#*! +)&,! '-$)#&,%'-5:! $%(#*1&'-&%$! *#! 0%*%.)/)-8! -*&)2&6(#6'!

%..%/&! )*! &,)1! =->^! &6(#6'! (#$%8?! ",%! /#(0)*-&)#*! #.! /%&67)(-0<! B34C! -*$!

.'-/&)#*-&%$! '-$)#&,%'-5:! ,-1! 1,#+*! 5'#()1)*9! -*&)2&6(#6'! %..%/&1! -*$! +-''-*&1!

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jNo lymph node metastases by final day of experiment!

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Table 4.1

")(%!I$-:1N!&#!$%D%8#5(%*&!#.!8:(5,!*#$%!(%&-1&-1%1<!#'!%*$!#.!%75%')(%*&!.#'!

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&,%!%75%')(%*&?!",'%%!$#1%!8%D%81!#.!'-$)#&,%'-5:!1&6$)%$k!T\F:!)*!KF:!5%'!.'-/&)#*!

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G-$)#&,%'-5:!+-1!-$()*)1&%'%$!-8#*%!-*$!)*!/#(0)*-&)#*!+)&,!/%&67)(-0!IB%&N<!T(9!

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TLL(9`A9!)?5?!+%%A8:!.#'!K!$#1%1?!

156

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157

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158

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159

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162

CHAPTER 5

Pathophysiological correlates of volumetric

DCE-CT in resected lung cancers.

!

5.1 Aims

! "#! $%&'()*%+! ,+$&+$-! &+$-$! *%! '! -$)'&*#.%+*/! ($&,$$.! 0#)12$&-*3! 45.'2*3!

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5.2 Introduction

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164

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"+*%! 1&*)*%$4! *.;+#1%$! 4*6*&')! 2*3-#%3#/5! %#=&,'-$J! '.4! $.'()$4! &+$! $)*2*.'&*#.! #=!

#(%$-0$-!$--#-J!'%!,$))!'%!'!-$413&*#.!*.!%'2/)*.6!$--#-B!@*2*)'-!4*6*&*%$4!&$3+.*\1$%!

4$=*.*.6!&+$!-$)'&*0$!#-!2$'.!&#&')!0'%31)'-!'-$'J!,*&+!0'%31)'-!%&'*.%J!%13+!'%!98V_!

#-!98VRJ!+'0$!($$.!1%$4! *.3-$'%*.6)5!'%!'!2$'%1-$!#=! &12#1-!0'%31)'-*&5! *.!(#&+!

/-$3)*.*3')!%&14*$%J! *.3)14*.6!2'22'-5!3'-3*.#2'!'.4!.$1-#()'%&#2'!2#4$)%J!'.4!

*.! 3)*.*3')! %&14*$%J! *.3)14*.6! ?@9A9J! ()'44$-! '.4! (-$'%&! 3'.3$-%! 7L9+'.&-'*.! $&!

176

')BJNOOVPJ!LI-*#.!$&!')BJ!NOOVPJ!LI-*#.!$&!')BJ!NOOdPJ!Lh$%&$-!$&!')BJRSSSPJ!L@1))*0'.!$&!')BJ!

NOOSP<B!!

!

Q.!1.$>/$3&$4!=*.4*.6!=-#2!&+*%!%&145!,'%!&+$!)'3K!#=!%*6.*=*3'.&!3#--$)'&*#.!($&,$$.!

&+$! -$)'&*0$! 0'%31)'-! '-$'! 798V_! =-'3&*#.<! '.4!'.5! #=! &+$!89:;9"!/'-'2$&$-%B! I.!

K$$/*.6! ,*&+! &+*%! =*.4*.6J! '! -$3$.&! /-$3)*.*3')! %&145J! ,+$-$! 4*6*&')! 2*3-#%3#/*3!

*2'6$%! ,$-$! 3'/&1-$4! '.4! '.')5%$4! 1%*.6! I2'6$c! %#=&,'-$! =-#2! &+$! ?'&*#.')!

I.%&*&1&$%! #=!M$')&+! *.!g$&+$%4'J! ')%#! ='*)$4! &#! 4$2#.%&-'&$! '! 3#--$)'&*#.! ($&,$$.!

)12*.')!0$%%$)!'-$'!'.4!9"!/$-=1%*#.!/'-'2$&$-%J!*.3)14*.6!gHJ!F@!'.4!gD!7F'-K!$&!

')BJ! NOOS<B! I.! &+*%! 3+'/&$-J! %*6.*=*3'.&! .$6'&*0$! 3#--$)'&*#.%! ,$-$! 4$2#.%&-'&$4!

($&,$$.! -$)'&*0$! 0'%31)'-! '-$'! 74$-*0$4! =-#2!98V_<! '.4!+5/#>*3! =-'3&*#.! 74$-*0$4!

=-#2!/*2#.*4'X#)$<J!3#.=*-2*.6!&+$!K.#,.!*.0$-%$!-$)'&*#.%+*/!($&,$$.!2*3-#0$%%$)!

4$.%*&5!'.4!+5/#>*'!*.!&12#1-%B!!

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"+$! 3#2/'-*%#.! ($&,$$.! *221.#+*%&#3+$2*%&-5! '.4! 89:;9"J! $%/$3*'))5! ,+$.!

1.4$-&'K$.! #.! '! ,+#)$! &12#1-! ('%*%J! /-#0*4$%! 3+'))$.6$%B! "+$! -$*.=)'&*#.! #=! &+$!

-$%$3&$4! %/$3*2$.! ,*&+! =#-2')*.! 3'..#&! '331-'&$)5! -$3-$'&$! &+$! #-*6*.')! %*X$! '.4!

%+'/$!*.!0*0#!'.4!&+$!/-#3$%%!#=!/'-'==*.!$2($44*.6!-$%1)&%!*.!&*%%1$!%+-*.K'6$!'.4!

4*%&#-&*#.B! I.! &+*%! %&145J! /'-'==*.;$2($44$4! %$3&*#.%! #=! _r2! &+*3K.$%%!,$-$! ($*.6!

3#2/'-$4! &#! U22! 9"! %$3&*#.%J! &+$! %2'))$%&! %$3&*#.! %*X$! &+#16+&! &#! ($! =$'%*()$J!

,*&+#1&!%'3-*=*3*.6!&+$!'331-'35!#=!&+*%!89:;9"!&$3+.*\1$B!"#!2*.*2*X$!&+$!/#&$.&*')!

*.'331-'3*$%J! ,$! -$#-*$.&'&$4! '))! #=! &+$! -$%$3&$4! )1.6! %/$3*2$.%! *.&#! &+$! %'2$!

/#%*&*#.%!'%!&+$5!+'4!($$.!*.!%*&1!'.4!&+$.!%$3&*#.%!,$-$!31&!*.!&+$!%'2$!/)'.$!'%!

&+$! &-'.%'>*')! 9"! %)*3$%B! G%*.6! &+$! #-*$.&'&*#.! #=! &+$! %)*3$%! #(&'*.$4J! 7,+*3+! ,'%!

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3#2/'-*%#.! #.! &+$! )'5$-! )$0$)! ,$-$! %$)$3&$4B! 8$%/*&$! &+$%$! $==#-&%J! *.+$-$.&!

*.'331-'3*$%! %&*))! $>*%&J!,+*3+! +'0$! &#! ($! &'K$.! *.&#! '33#1.&!,+$.! *.&$-/-$&*.6! &+$!

-$%1)&%! =-#2! &+*%! %&145B! D#-! &12#1-! gDJ! 2$'%1-$2$.&! ,'%! =-#2! '! 3$.&-')! U22!

177

&12#1-! %)*3$! #.)5J! 41$! &#! &$3+.*3')! )*2*&'&*#.%! *2/#%$4! (5! &+$! 9"! %3'..$-!

3#.=*61-'&*#.! 7RY! Z89"<J! '.4! &+*%! /-#+*(*&$4! (#&+! &+$! 21)&*/)$! )'5$-! '.4! ,+#)$!

&12#1-!'.')5%*%!1%$4!=#-!&+$!#&+$-!89:;9"!'.4!D8E;F:"!/'-'2$&$-%B!

!

I.! &+$! '%%$%%2$.&! #=! )1.6! &12#1-! 0'%31)'-*&5! '.4! +5/#>*'J! 9"! +#)4%! '40'.&'6$%!

#0$-!ZaIB!h*&+!='%&$-!%3'.!%/$$4%J!4*%&#-&*#.!=-#2!-$%/*-'&#-5!2#0$2$.&!*%!)$%%!#=!'!

/-#()$2! '.4J! '%! ,*&+! &+*%! %&145J! *&! )$.4%! *&%$)=! &#! &+$! 1%$! #=! (-$'&+! +#)4*.6! #-!

-$%/*-'&#-5;6'&$4!&$3+.*\1$%J! &+'&!$.'()$!%$\1$.&*')!%3'.%!&#!($!4#.$!*.!&+$!%'2$!

/+'%$!#=!-$%/*-'&*#.B!"+*%!*%!*.!'44*&*#.!&#!&+$!6##4!%/'&*')!-$%#)1&*#.!*&!'==#-4%!'.4!

&+$!-$)'&*0$)5!%&-'*6+&=#-,'-4!\1'.&*=*3'&*#.!,*&+!89:;9"B!D#-!$>&-'&+#-'3*3!4*%$'%$!

%*&$%J!=1.3&*#.')!ZaI!&$3+.*\1$%!+'0$!($$.!1%$4!%133$%%=1))5!*.!&+$!*4$.&*=*3'&*#.!#=!

*.&-'&12#1-')!+5/#>*'J!'%!4$&$3&$4!(5!/*2#.*4'X#)$B!g)##4!#>56$.!)$0$)!4$/$.4$.&!

7gjA8<;ZaI! +'%! ($$.! 1%$4! *.! /-#%&'&$! 3'.3$-J! ,+$-$! a7N<s! 4*%/)'5$4! '! +*6+!

%$.%*&*0*&5J! '.4! '! .12($-! #=! 89:;ZaI! /'-'2$&$-%! +'0$! %+#,.! %&'&*%&*3'))5!

%*6.*=*3'.&!3#--$)'&*#.%!*.!+$'4!'.4!.$3K!3'.3$-!7LM#%K*.!$&!')BJ!NOO[PJ!L?$,(#)4!$&!

')BJ! NOOSP<B! h$! +'0$! 4$2#.%&-'&$4! *.! &+*%! %&145J! &+'&! 0#)12$&-*3! 89:;9"! %+#,%!

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(*#2'-K$-!#=!+5/#>*'! *.!?@9A9J!,*&+!1%$%!%13+!'%!2#.*&#-*.6!&+$!$==$3&%!#=!.#0$)!

&'-6$&$4! &+$-'/*$%J! 6*0$.! ')#.$! #-! *.! 3#2(*.'&*#.! ,*&+! -'4*#&+$-'/5J! '.4! ,*&+!

3#.0$.&*#.')! 35&#&#>*3! 3+$2#&+$-'/*$%B! "+$-$! *%! ')%#! &+$! /#%%*(*)*&5! &+'&! &+*%!

&$3+.*\1$! 3'.! ($! +'-.$%%$4! *.&#! &+$! -'4*#&+$-'/5! /)'..*.6! /-#3$%%J! &#! *4$.&*=5!

+5/#>*3! %1(0#)12$%!,*&+*.!?@9A9! &12#1-%J!,+*3+! 3'.! &+$.! ($! &'-6$&$4! (5! 4#%$!

/'*.&*.6! &$3+.*\1$%J! 4$)*0$-*.6! +*6+$-! -'4*'&*#.! 4#%$%! &#! 3#2('&! &+$! -$)'&*0$!

-'4*#-$%*%&'.3$!*.!&+$%$!-$6*#.%B!!

!

178

g#&+!89:;9"!'.4!D8E;F:"!/'-'2$&$-%!2'5!($!1%$4!&#!'*4!*.!&+$!*4$.&*=*3'&*#.!#=!

/##-! /-#6.#%*%! &12#1-%! '.4! /-#0*4$! =1-&+$-! *.=#-2'&*#.! =#-! &+$! %&-'&*=*3'&*#.! #=!

/'&*$.&%! /-*#-! &#! %1-6*3')! -$%$3&*#.! #-! -'4*#&+$-'/5B! "+$! %*6.*=*3'.&! *.0$-%$!

3#--$)'&*#.!($&,$$.!F@!'.4!(#&+!E)1&;R!'.4!@GH2'>J!/#*.&%!&#!)#,!0')1$%!=#-!,+#)$!

&12#1-!F@!'%!'.!*.4*3'&#-!#=!/##-!/-#6.#%*%!*.!?@9A9B!@*6.*=*3'.&!4*==$-$.3$%!*.!F@!

'.4! @GH2'>J! 4$2#.%&-'&$4! ($&,$$.! '4$.#3'-3*.#2'%! '.4! %\1'2#1%! 3$))!

3'-3*.#2'%J!'.4!&+$!%*6.*=*3'.&)5!6-$'&$-!gDJ!%$$.!*.!+*6+$-!%&'6$!'.4!.#4$!/#%*&*0$!

?@9A9J!3#2/'-$4!&#!%&'6$!I!'.4!.#4$!.$6'&*0$!3'%$%!-$%/$3&*0$)5J!')%#!/#*.&!&#!&+$!

1%$!#=!&+$%$!/'-'2$&$-%!'%!/-#6.#%&*3!(*#2'-K$-%!*.!&+$%$!&12#1-%B!

!

5.6 Conclusion

"+$!4'&'!/-$%$.&$4!*.!&+*%!3+'/&$-!+'%!4$2#.%&-'&$4!&+$!/#&$.&*')!'(*)*&5!&#!\1'.&*=5!

,+#)$! &12#1-! +5/#>*'! *.! ?@9A9! 1%*.6! 0#)12$&-*3! 89:;9"f! &+$! /'-'2$&$-! #=! gH!

3#--$)'&$%!.$6'&*0$)5!,*&+!&+$!+5/#>*3!=-'3&*#.J!'%!4$=*.$4!(5!/*2#.*4'X#)$J!'.4!F@!

3#--$)'&$%! .$6'&*0$)5! ,*&+! &+$! +5/#>*3! =-'3&*#.J! '%! 4$=*.$4! (5! E)1&;RB! "+$!

4$/$.4$.3$! #=! &+$! D8E;F:"! /'-'2$&$-J! @GH2'>J! #.! (#&+! E)1&;R! '.4! -$413$4!

&12#1-!0'%31)'-! )$'K'6$!7F@<!,'%!+*6+)*6+&$4B!8*==$-$.3$%!,$-$!-$0$')$4!($&,$$.!

&+$!%1(&5/$%!#=!?@9A9J!,*&+!6-$'&$-!%&'*.*.6!#=!E)1&;R!3#2/'-$4!&#!/*2#.*4'X#)$!*.!

@99%!'.4!&+$!-$0$-%$!/*3&1-$!%$$.!,*&+!'4$.#3'-3*.#2'%B!

!

G%*.6!.#0$)!4*6*&*%'&*#.!#=!2*3-#%3#/$! *2'6$%J!,*&+! *.!+#1%$!%#=&,'-$J! &+$! *.0$-%$!

-$)'&*#.%+*/! ($&,$$.! &+$! -$)'&*0$! 0'%31)'-! '-$'! '.4! +5/#>*3! =-'3&*#.%! *.! ?@9A9!

,$-$!3#.=*-2$4B!M#,$0$-J!.#!4*-$3&!3#--$)'&*#.!($&,$$.!-$)'&*0$!0'%31)'-!'-$'!'.4!

'.5!#=! &+$!89:;9"!/'-'2$&$-%!,'%!#(%$-0$4B!"+*%!2'5!($!'!3#.%$\1$.3$!#=! &+$!

%2'))! .12($-%! #=! /'&*$.&%! *.! &+*%! %&145! #-! 41$! &#! &+$! *.+$-$.&! *.'331-'3*$%! #=! &+$!

&$3+.*\1$C! 3#2/'-*%#.! ($&,$$.! _r2! &+*3K! +*%&#)#6*3')! %$3&*#.%! '.4! U22! 9"!

%$3&*#.%f! %+-*.K'6$! '.4! 4*%&#-&*#.! #=! -$%$3&$4! &*%%1$f! 4*==*31)&*$%! *.! %$)$3&*#.! #=!

179

3#--$%/#.4*.6! 9"! %)*3$f! /#&$.&*')! .#-2')! )1.6! 0'%31)'&1-$! *.3)1%*#.! *.! 89:! 9"!

'.')5%*%B!

!

"#! =1))5! -$')*%$! &+$! /#&$.&*')! #=! 0#)12$&-*3! 9"! '%! '! (*#2'-K$-! #=! *.&-'&12#1-')!

+5/#>*'!*.!?@9A9J!=1-&+$-!,#-K!*%!-$\1*-$4!&#!%$$!,+$&+$-!&+$!%'2$!3#--$)'&*#.%!'-$!

#(%$-0$4!,+$.!$>'2*.*.6!%2'))!%1(0#)12$%!#=!U22V!#-!)$%%B!"+*%!,#1)4!'))#,!*&!&#!

($! 1&*)*%$4! =#-! 4#%$! /'*.&*.6! &$3+.*\1$%J! *.! &+$! /)'..*.6! #=! 3#2/)$>! -'4*#&+$-'/5!

&-$'&2$.&%B!I.!/-#0*4*.6!'331-'&$!=1.3&*#.')!4'&'!#.!?@9A9J!0#)12$&-*3!89:;9"J!*.!

'44*&*#.! &#! D8E;F:"J! +'%! &+$! /#&$.&*')! &#! ($! +'-.$%%$4! '%! '! &##)! &#! '*4! &+$!

/-#6.#%&*3!%&-'&*=*3'&*#.!#=!/'&*$.&%!'.4!%$)$3&*#.!=#-!&-$'&2$.&B!

180

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Q4$.#3'-3*.#2'! Y!7_V<!

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Grade !

N! d!7U[<!

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?O! Y!7_V<!

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!

!

Table 5.1

@&'6*.6!'.4!+*%&#/'&+#)#6*3')!=$'&1-$%!#=!R_!-$%$3&$4!?@9A9!&12#1-%B!

181

A

U RO RU NO

OBOO

OBOU

OBRO

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OBNO

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OBO

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C

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OBO

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OBV

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!Figure 5.1

9#--$)'&*#.!#=!2$'.!89:;9"!4$-*0$4!()##4!0#)12$!7gH<!,*&+!&+$!=-'3&*#.!%&'*.$4!=#-!

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&-'.%/#-&$-;R!7E)1&;R<!'.4!C!/*2#.*4'X#)$!7F*2#<B!

182

A!

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OBOO

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OBNO

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!B

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g#&&#2Z*44)$"#/

!C

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798V_<J!B!6)13#%$!&-'.%/#-&$-;R!7E)1&;R<!'.4!C!/*2#.*4'X#)$!7F*2#<B!

183

A

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184

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!B

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185

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F@! kOBN[d! p=0.117 k;OB_SY p=0.002* k;OBOVR p=0.856

gD! k;OBOUU! p=0.881 kOBRVV! p=0.683 kOBNSR! p=0.358

@GH2'>! k;OBNRN! p=0.235 kOBV_d! p=0.041* k;OBVVR p=0.049*

s%*6.*=*3'.&!'&!Um!)$0$)! ! ! ! ! !

Table 5.2

@/$'-2'.! -'.K! 3#--$)'&*#.%! #=! 2$'.! 89:;9"! 4$-*0$4! ()##4! 0#)12$! 7gH<J!

/$-2$'(*)*&5! %1-='3$! '-$'! /-#413&! 7F@<J! ()##4! =)#,! 7gD<! '.4! 2'>*212! %&'.4'-4!

1/&'K$! 0')1$! 7@GH2'><! ,*&+! &+$! =-'3&*#.! %&'*.$4! =#-! V! 4*==$-$.&!

*221.#+*%&#3+$2*3')! %&'*.%C! $.4#&+$)*')! 2'-K$-! 798V_<J! 6)13#%$! &-'.%/#-&$-;R!

7E)1&;R<!'.4!/*2#.*4'X#)$!7F*2#<B!

186

A


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Figure 5.5

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187

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188

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189

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190

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191

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192

!

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193

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194

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!

195

CHAPTER 6

Tumour vascular effects of combined vascular

disruption and radiation in advanced NSCLC

6.1 Aims

To determine the reproducibility and repeatability of the volumetric DCE-CT

technique in assessing whole tumour vascular changes in advanced NSCLC.

To determine tumour vascular effects of high dose palliative radiotherapy in

combination with twice weekly combretastatin A-4 phosphate in advanced

NSCLC, using volumetric DCE- CT.

6.2 Introduction

In this chapter, clinical experiments using DCE-CT assessment of the tumour

vascular changes in patients receiving the VDA CA4P, in addition to radiotherapy,

for advanced NSCLC are described.

Around 65% of cases of NSCLC present with advanced disease, either Stage IIIB or

IV. Only 15 to 25% of cases are deemed to be potentially curable by surgical

resection or radical radiotherapy (Lester et al., 2006). For the remainder of cases

non-curative treatments and supportive care are the available treatment options,

with radiotherapy commonly used as a palliative treatment. It was estimated in 1993

that in the UK 20-30% of cases of NSCLC received palliative radiotherapy (Maher et

196

al., 1993). Many different palliative radiotherapy doses and fractionations are

currently in clinical use. A high dose palliative lung radiotherapy fractionation,

delivering 27Gy in 6# over 3 weeks, has been developed at Mount Vernon Hospital,

Middlesex, UK. In a retrospective study it was shown to have achieved symptomatic

improvement in 48% of those treated; median survival was 8 months, 1 year overall

survival was 27% and no grade 3 or 4 toxicities were observed (Corner et al., 2007).

This radiotherapy fractionation was selected for use in this study as it lends itself to

the planned escalation of CA4P dose intensity, from single dose up to twice weekly

administration for the duration of the radiotherapy treatment.

It is well documented that timing, sequence and schedule are of particular

importance when combining vascular directed therapies with radiotherapy. In

preclinical studies, the administration of CA4P after or simultaneously with

radiotherapy has been shown to improve tumour control, but when given prior to

radiotherapy this beneficial effect was lost (Murata et al. 2001a). A twice weekly

fractionation offers a minimum 72 hour recovery period after each dose of CA4P,

therefore avoiding this potential negative effect, by allowing tumour cell

reoxygenation following the acute CA4P-induced vascular shutdown. Volumetric

DCE-CT has been used for all 3 NSCLC treatment cohorts in this phase IB study, to

facilitate comparison of the whole tumour vascular effects, resulting from twice

weekly CA4P scheduling with the weekly and single dose scheduling from the

previous 2 cohorts.

6.3 Methods

6.3.1 Patient selection and recruitment

All patients were recruited as part of a “Phase 1b trial of CA4P (combretastatin A-4

phosphate) in combination with radiotherapy in patients with advanced cancer of the

197

lung, head & neck or prostate: CA4P protocol number UKR104”; the full inclusion

and exclusion criteria of which are shown in Appendix B. Trial recruitment

commenced in January 2003 following ethical and MHRA approval. Explicit approval

for the exposure of patients to radiation for research purposes was granted, as

required by the IR(ME)R (The Ionising Radiation (Medical Exposure) Regulations

2000) legislation. Each patient gave written informed consent, prior to undergoing

screening to determine suitability for participation in this study.

The analysis of one cohort of the UKR-104 trial (cohorts 7) is reported in this

chapter, the treatment scheduling of which is shown in Table 2.1. Patients with

histologically proven advanced NSCLC (Cohort 7) deemed unsuitable for radical

treatment, were prospectively recruited. Having fulfilled the criteria for inclusion in

the study, patients proceeded to receive high dose hypofractionated palliative lung

radiotherapy, 27Gy in six fractions over 3 weeks (as per section 2.2.1.1). This was

delivered in combination with CA4P (as per section 2.2.2), 50mg/m2 i.v.,

administered after every fraction of radiotherapy. Each patient was scheduled to

receive a total of 6 doses of CA4P, the final dose level of a dose escalation study.

Comparative analysis between the results from cohort 7 and the previously reported

NSCLC cohorts 1 and 2 was undertaken. The first cohort (cohort 1) had received a

single dose of CA4P, at a dose of 50mg/m2 i.v. administered following the second

fraction of radiotherapy only and cohort 2 had received weekly CA4P, 50mg/m2 i.v.

given after the second, fourth and sixth fractions of radiotherapy. Data from a further

NSCLC radiotherapy alone cohort were also included when examining the impact of

changes in technique reproducibility.

198

6.3.2 Imaging

DCE-CT was performed as described in section 2.3.1. Volumetric DCE-CT of the

thorax (as per section 2.3.1.1) was selected to assess changes in lung tumour

vascularity, on a whole tumour basis, resulting from the combination treatment

described above. Eight DCE-CT scans were performed for cohort 7 as follows: 2

baseline pretreatment scans; further scans at 1 hour after radiotherapy (1 hour prior

to administration of CA4P) and another at 4 hours after administration of CA4P were

scheduled with the second, fourth and sixth fractions of radiotherapy and doses of

CA4P.

6.3.3 Statistical analysis

Statistical comparison of changes in the DCE-CT derived parameters (blood volume

and permeability surface area product) between time points were assessed using

reproducibility analysis, as per section 2.3.1.3. To allow assessment of

measurement reproducibility, the two initial pretreatment perfusion studies from

each patient were analysed by the same observer for both studies, cross-

referencing between studies from the same patient to ensure similar tumour levels.

This reproducibility statistic enabled the calculation of whether a change in blood

volume or permeability surface area product post treatment for an individual patient

or a group of patients was statistically significant.

6.4 Results

6.4.1 Lung Volumetric DCE- CT

Six patients were treated in cohort 7: 3 males and 3 females, mean age 71 years

(Range 61 to 83 years). The combination treatment was well tolerated, with no dose

limiting toxicities (DLTs) produced. All of the six patients received the intended 6

199

fractions of radiotherapy, 6 doses of CA4P and underwent volumetric DCE-CT

scanning as planned; there were 48 CT studies for analysis from the 6 patients

treated. An example of the colour DCE-CT parametric maps for 1 patient is shown in

Figure 6.1.

6.4.2 Reproducibility

The reproducibility statistics for both blood volume and permeability surface area

product are shown in Table 6.1. These were derived from the baseline volumetric

DCE-CT scans from 24 patients with NSCLC in the UKR-104 study; 6 patients in

cohort 1, 4 patients in cohort 2, 6 patients in cohort 7 and 8 patients in a

radiotherapy alone control group. The Kendall’s tau test confirmed the

proportionality of error on the mean value for both parameters, indicating

dependence of error on the mean. As a result of this, both parameters were

logarithmically transformed.

The percentage group change, in each parameter resulting from therapy, required to

achieve significance at the 95% level, was calculated for the different cohort sizes.

For blood volume a change greater than –21.5% to 27.4% was required for cohort 7

(n=6), a change greater than –18.9% to 23.4% for the combined cohorts 1 and 2

(n=8), and a change greater than –25.7% to 34.6% was required for cohort 2 alone

(n=4). For permeability surface area product a change greater than –11.4% to

12.9% was required for cohort 7 (n=6), a change greater than –10.0% to 11.1% for

the combined cohorts 1 and 2 (n=8), and a change greater than –13.8% to 16.0%

required for cohort 2 alone (n=4).

200

6.4.3 Blood Volume

The blood volume (BV) results for the 6 patients in cohort 7 and the mean values

and standard deviations for the cohort, at each of the time points where DCE-CT

was performed, are shown in Tables 6.2 and 6.3. These results were then plotted to

produce the graph seen in Figure 6.2.

In this cohort, following the second fraction of radiotherapy (2# RT), having received

both the first fraction of radiotherapy and first dose of CA4P 3 days earlier, the mean

blood volume increased significantly by 42.2%. Four of the 6 patients in the cohort

had a rise in BV between these time points, yet only patient, BS37, had a significant

individual increase (193.6%). A reduction in BV was seen for 4 patients after the

second dose of CA4P (CA4P2), compared to 1 hour after the second fraction of

radiotherapy. However, differing effects in BV were observed between these time

points, with patient BS37 having a significant individual reduction of -57.5%,

whereas patient JW35 had a significant individual rise of 110.9%. There were no

significant individual changes after the second dose of CA4P compared to the mean

baseline (MB). The only other group change observed that was significant on

reproducibility testing was the change in blood volume after the sixth fraction of

radiotherapy compared with 4 hours after the fourth dose of CA4P (CA4P4), with a

mean increase of 36.8%.

Further significant individual changes in blood volume compared to previous time

points were observed for patient JW35: a reduction of -48% at 4 hours after the

fourth dose of CA4P, an increase of 259% after the sixth fraction of radiotherapy (6#

RT) and a reduction of -50.7% at four hours after the sixth dose of CA4P (CA4P6).

Again compared to previous time points, patient RD32 had a significant individual

decrease of -74.3% after the sixth fraction of radiotherapy, and a significant

201

individual increase of 107.4%, 4 hours after the sixth dose of CA4P. Further to this,

patient RD32 had a significant increase of 118.8% 4 hours after the fourth dose of

CA4P, compared to mean baseline. The only other significant change seen was

patient AA34 after the fourth fraction of radiotherapy, with a reduction of -47.1%,

compared to mean baseline.

The blood volume (BV) results for 8 patients from cohorts 1 and 2, in addition to the

group mean values for the combined cohorts, are shown in Tables 6.4 and 6.5.

These results were then plotted to produce the graph seen in Figure 6.3. There were

no significant group changes compared with either mean baseline or the previous

time point, for any of the eight patients. The only significant individual change

produced was a reduction of 46.9% compared to mean baseline, with patient HC07

at 1 hour after the sixth fraction of radiotherapy (6# RT).

6.4.4 Permeability surface area product

The permeability surface area product (PS) results for the 6 patients and the mean

values and standard deviations for the cohort, at each of the time points where

DCE-CT was performed, are shown in Tables 6.6 and 6.7. These results were then

plotted to produce the graph seen in Figure 6.4.

A significant group increase of 20.3% in the whole tumour permeability surface area

product was seen 1 hour after the second fraction of radiotherapy (2# RT), the

patients having received both the first fraction of radiotherapy and first dose of CA4P

3 days earlier. Of the 6 patients in cohort 7, 4 had a rise in PS, with patient BS37

having a significant individual increase (77.8%), compared to mean baseline (MB),

and one patient showing no change. At 4 hours after the second dose of CA4P

(CA4P2) compared to after the second fraction of radiotherapy, PS was reduced for

5 out of the 6 patients, patient BS37 having a significant individual reduction of -

202

30%. However, patient RD32 was noted to have a significant rise (50%) at this time

point, compared to after the second fraction of radiotherapy and mean baseline;

these 2 values being identical.

After the fourth fraction of radiotherapy (4# RT), the patients having received 3

doses of CA4P previously, 4 of the 6 patients showed an increase in PS. The

increase for patient JS33, was significant compared to 4 hours after the second

dose of CA4P (35.5%) and also mean baseline (40%). However, a significant

individual decrease in whole tumour PS (–33.3%), compared to 4 hours after the

second dose of CA4P, was also observed at this time point for patient RD32. The

only other significant group changes observed after this point were a rise of 14.8%

at 4 hours after the fourth dose of CA4P (CA4P4) and a rise of 14.6% after the sixth

dose of CA4P (CA4P6), both significant in comparison with mean baseline. Patient

JW35 had a significant individual decrease in PS after the sixth fraction of

radiotherapy (6# RT), compared with the previous time point (–27.3%) and with

mean baseline (54.4%). At the same time point, a significant increase in PS was

noted for patient AA34 (37.9%), in comparison to mean baseline, with this significant

increase maintained at 4 hours after the subsequent sixth dose of CA4P. Patient

AL31 had significant decreases in PS, compared to mean baseline, at 4 hours after

the fourth dose of CA4P (-26.0%) and after the sixth fraction of radiotherapy (-

39.7%).

The permeability surface area (PS) results for 8 patients from cohorts 1 and 2, in

addition to the mean values for the combined cohorts, are shown in Tables 6.8 and

6.9. These results were then plotted to produce the graph seen in Figure 6.5.

Significant group changes were seen 1 hour after the second fraction of

radiotherapy (2# RT) compared to mean baseline (MB), with a 14.6% increase in

whole tumour PS. A significant group increase of 18.9% was also produced 1 hour

after the fourth fraction of radiotherapy (4#RT), compared to 4 hours after the first

203

dose of CA4P (CA4P1). Significant individual changes in PS were also observed in

cohorts 1 and 2. Significant rises were seen in PS after the second fraction of

radiotherapy, compared with mean baseline, for patients FR03 (45.3%) and SF06

(39.38%), although 4 hours after the first dose of CA4P they had changes in

different directions, with a significant decrease (–31.4%) compared with the previous

time point and a significant rise (74.1%) compared to mean baseline, respectively.

Patient SD12 had a significant decrease in PS after the first dose of CA4P,

compared to 1 hour after the second fraction of radiotherapy (-42.2%) and mean

baseline (-34.9%). Following this decrease, patient SD12 then had a significant

increase in PS of 49.8% 1 hour after the fourth fraction of radiotherapy (4# RT),

compared with the previous time point. The only other significant individual change

was patient HC07, where a reduction of –29.9% was seen after the sixth fraction of

radiotherapy (6# RT) compared to 4 hours after the second dose of CA4P (CA4P2).

6.5 Discussion

Volumetric DCE-CT, an imaging biomarker of tumour vascularity, is being used

increasingly to assess treatment related changes in tumour vasculature. DCE-CT

has been used in this context in clinical trials of anti-angiogenic and other vascular

directed therapies, including bevacizumab, endostatin, SU6668, L-NNA and the

combination of AZD2171 and gefitinib ([Willett et al., 2004], [Thomas et al., 2004],

[Xiong et al., 2004], [Ng et al., 2007c], [Meijerink et al., 2007]). Whole tumour

measurements, have been made possible by novel volumetric techniques, which

enable superior assessment of the spatial heterogeneity that exists within tumours.

Previously some early phase clinical trials utilising volumetric techniques have

examined the vascular effects in NSCLC of radiotherapy alone and in combination

with a single dose of CA4P ([Ng et al., 2007b], [Ng et al., 2007a]). In this work, we

204

have built upon these previous studies, assessing the changes resulting from

treatment with radiotherapy and the increased dose intensity of CA4P: from single

dose to weekly then twice weekly. Whilst this chapter focuses on the final cohort of 6

patients, within the whole UKR-104 study there were 24 NSCLC patients with the

required two baseline scans, derived from 3 treatment and 1 control cohorts, from

which reproducibility could be assessed, to determine the extent of treatment-related

change required to indicate significance on an individual and group basis. This was

done for whole tumour blood volume and permeability surface area product in the

patients from the 3 treatment cohorts; with the increased number of patient data

providing more accurate assessment of the intra-tumoural variability in derived

parameters with the volumetric DCE-CT technique in NSCLC (Bland and Altman,

1996a,b,c). Given the marked heterogeneity that exists in tumour vascularity and

blood flow between different tumours and in the same tumour at different time

points, this is an important step. It also enables potential confounding patient

factors, including variability in cardiac output or haemoglobin, to be taken into

account. In addition to their role in the UKR-104 study, these measures of

reproducibility will allow the significance of changes in volumetric DCE-CT

parameters in NSCLC to be assessed in future studies utilising this technique at our

centre.

For all the NSCLC treatment cohorts in this study, the first DCE-CT scan during

treatment was performed after the second fraction of radiotherapy. This provides an

interesting point for comparison as cohort 7 had already received a dose of CA4P

following the first fraction of radiotherapy, whereas cohorts 1 and 2 had not received

any prior CA4P. A significant group increase in blood volume was seen for cohort 7,

yet not the first 2 cohorts. The only patient to have a significant individual rise in

blood volume was also in cohort 7. Receiving a dose of CA4P 72 hours previously

did not impede this increase in blood volume, which could be due to greater blood

205

flow in the remaining larger vessels, resulting from the smaller and more immature

blood vessels of the tumour being damaged by CA4P (Tozer et al., 2001). This

effect on tumour blood volume was not seen in cohort 2 after the fourth fraction of

radiotherapy, when they had received a dose of CA4P 1 week previously. It would

suggest that this improvement in tumour blood flow in larger vessels post CA4P is

due to a transient functional change, with a return to the more chaotic vascular state

after 1 week. However, it could be that, as only 4 patients had volumetric DCE-CT

scans in cohort 2, a similar effect is produced but has not been detected due to the

small sample size.

A different pattern was observed with permeability surface area product after the

second fraction of radiotherapy. Significant group increases were seen in cohort 7

and also in cohorts 1 and 2, seemingly independent of whether they had received a

previous dose of CA4P or not. A further significant group increase in permeability

surface area product after the fourth fraction of radiotherapy was observed with

cohorts 1 and 2, but was not seen in cohort 7 or in any of the cohorts after the sixth

fraction of radiotherapy. This suggests that it is the first dose of concurrent CA4P

that has the greatest effect, further enhancing the increase in permeability of the

tumour vasculature resulting from radiotherapy. The diminishing of this effect with

further doses of CA4P may arise from the loss of small blood vessels within the

tumour, due to the CA4P-induced disruption of interphase microtubules in

endothelial cells; these small vessels being more sensitive to its vascular disruptive

effects (Tozer et al., 2001).

Indicative of the expected vascular shutdown produced by VDAs, individual

decreases in whole tumour blood volume were produced at 4 hours following the

administration of CA4P for 4 of the 6 patients in cohort 7 (after the second dose of

CA4P) and 5 of the 8 patients in the combined cohorts 1 and 2 (after the first dose of

206

CA4P). Despite this, the only significant decreases were observed in cohort 7 and

occurred in patients where significant individual increases in blood volume had been

previously observed, following the commencement of radiotherapy. These findings

are in keeping with sensitisation of the tumour vasculature to the effects of CA4P by

radiotherapy, an effect that may be more pronounced in tumours sensitive to the

effects of CA4P. Tumours with increased vascular permeability have been shown to

be more susceptible to vascular disruptive therapies and in these experiments we

have seen that radiotherapy increases both tumour blood volume and permeability

(Beauregard et al., 2001). It is possible that these vascular changes reflect

treatment-induced enhanced endothelial cell damage, adding support for combining

CA4P and radiotherapy, especially as radiation-induced damage to the tumour

vasculature is known to be an important determinant of tumour cell survival (Garcia-

Barros et al., 2003).

In preclinical studies, CA4P has been shown to increase tumour vascular

permeability through disruption of the molecular engagement of endothelial cell-

specific junctional molecules, including VE-cadherin (Vincent et al., 2005).

Significant rises in permeability surface area product after CA4P were seen with

patients RD32 and JW35, followed by a significant decrease after the subsequent

fraction of radiotherapy, yet patient BS37 displayed the exact opposite effect with a

decrease after CA4P and a rise after radiotherapy. The twice weekly scheduling of

concurrent CA4P (cohort 7) produced a significant rise in permeability surface area

product for 5 of the 6 patients, compared with only 2 of the eight patients receiving a

once weekly schedule of CA4P (cohorts 1 and 2). This difference is, however, not

statistically significant and whether a true additive benefit is being observed with the

more dose dense regimen remains uncertain.

207

6.5 Conclusion

In this experiment we were able to detect significant treatment-induced changes in

both whole tumour blood volume and permeability surface area product in these

cases of NSCLC. Through inclusion of DCE-CT data from 24 patients, we were able

to accurately determine the reproducibility of the volumetric technique at our centre.

We have observed a greater proportion of significant group increases in blood

volume and permeability surface area product plus a greater number of significant

changes in these parameters in cohort 7, with the twice weekly scheduling of CA4P

combined with twice weekly fractions of radiotherapy, compared to the single dose

and weekly scheduling used in cohorts 1 and 2 respectively. The increase seen in

functional tumour vascular leakage after radiotherapy was, however, lost in the twice

weekly scheduling of CA4P after the second fraction, and was only present with the

weekly scheduling of CA4P after the fourth fraction.

Given the small number of patients in each treatment cohort, it is impossible to fully

establish the significance of these observed differences. It is very likely that

differences in tumour cell type, grade, stage and tumour volume may contribute to

these findings. Our data would support the hypothesis that enhanced endothelial cell

damage results from the combination of radiotherapy and concurrent administration

of CA4P in advanced NSCLC, without any significant overlapping or enhanced

acute toxicity. Further phase 2 studies are required to fully establish the role for this

combination therapy in NSCLC, using either weekly CA4P at a dose of 50mg/m2 for

standard daily radiotherapy fractionations (5 days per week) or, potentially, twice

weekly CA4P, at a dose of 50mg/m2, if using a twice weekly radiotherapy

fractionation, as in this study.

208

CA4P2 4# RT

2# RT Baseline

Figure 6.1

Colour parametric maps of DCE-CT derived whole tumour blood volume (BV) for

patient BS37, who received twice weekly CA4P and RT, as part of Cohort 7. The

yellow arrow points to the left apical lung primary tumour. An increase in blood

volume (compared to baseline) is seen in the lung tumour 1 hour after the second

fraction of radiotherapy (2# RT), then a decrease at 4 hours after the subsequent

(second) dose of CA4P (CA4P2), on the same day. In comparison to CA4P2, only

slight changes were observed in BV with the next DCE-CT scan, 1 hour after the

fourth fraction of radiotherapy (4# RT).

209

PS

(ml/100ml/min)

BV

(ml/100ml)

Mean (SD) 11.49 (4.05) 5.82 (2.14)

Mean difference 0.16 -1.19

95% limits of agreement -25.7% to 34.5% -44.8% to 81.1%

WSD 0.11a 0.21a

WCV (%) 11.3a 23.9a

Repeatability 0.30 0.59

aLn transformed data

SD – standard deviation; WCV – within subject coefficient of variation; WSD – within

subject standard deviation

Table 6.1 Reproducibility and repeatability statistics from paired studies performed on 24

patients, with NSCLC due to receive high dose palliative radiotherapy, measuring

whole tumour permeability surface area product (PS) and blood volume (BV).

210

MB 2#RT CA4P2 4#RT CA4P4 6#RT CA4P60

2

4

6

8

10

12

14

16

18

20

22B

lood

Vol

ume

(mL/

100m

L)

Time points

AL31 RD32 JS33 AA34 JW35 BS37 Mean

Figure 6.2

Graph of median whole tumour blood volume for NSCLC patients receiving twice

weekly CA4P and RT (Cohort 7), plotted at the following time points: MB- mean

baseline; 2# RT- 1 hour after second fraction of radiotherapy; CA4P2 – 4 hours after

the second dose of CA4P; 4# RT- 1 hour after fourth fraction of radiotherapy;

CA4P4 – 4 hours after the fourth dose of CA4P; 6# RT- 1 hour after sixth fraction of

radiotherapy; CA4P6 – 4 hours after the sixth dose of CA4P.

211

MB 2# RT change (%) CA4P2 change (%) 4# RT change (%)

AL31 7.20 10.00 38.89 8.10 12.50 6.20 -13.89

RD32 4.8 7.90 64.58 6.70 39.58 6.80 41.67

JS33 7.55 8.30 9.93 8.80 16.56 11.00 45.70

AA34 4.35 3.10 -28.74 2.90 -33.33 2.30 -47.13a

JW35 8.55 6.40 -25.15 13.50 57.89 7.50 -12.28

BS37 7.05 20.70 193.62a 8.80 24.82 9.10 29.08

Mean 6.58 9.40 42.19b 8.13 19.67 7.15 7.19

CA4P4 change (%) 6# RT change (%) CA4P6 change (%)

AL31 6.20 -13.89 8.20 13.89 8.20 13.89

RD32 10.50 118.75a 2.70 -43.75 5.60 16.67

JS33 10.30 36.42 7.70 1.99 11.80 56.29

AA34 3.40 -21.84 5.20 19.54 5.40 24.14

JW35 3.9 -54.39a 14 63.74 6.9 -19.30

BS37 8.30 17.73 6.30 -10.64 8.70 23.40

Mean 7.10 13.80 7.35 7.46 7.77 19.18

aSignificant individual change in BV bSignificant group change in BV

MB- mean baseline; 2# RT- 1 hour after second fraction of radiotherapy; CA4P2 – 4

hours after the second dose of CA4P; 4# RT- 1 hour after fourth fraction of

radiotherapy; CA4P4 – 4 hours after the fourth dose of CA4P; 6# RT- 1 hour after

sixth fraction of radiotherapy; CA4P6 – 4 hours after the sixth dose of CA4P.

Table 6.2

DCE-CT derived median blood volume (BV) values (ml/100ml) and percentage

change from mean baseline for NSCLC patients receiving twice weekly CA4P and

RT (UKR104 cohort 7).

212


AL31 7.20 10.00 38.89 8.10 -19.00 6.20 -23.46

RD32 4.8 7.90 64.58 6.70 -15.19 6.80 1.49

JS33 7.55 8.30 9.93 8.80 6.02 11.00 25.00

AA34 4.35 3.10 -28.74 2.90 -6.45 2.30 -20.69

JW35 8.55 6.40 -25.15 13.50 110.94a 7.50 -44.44

BS37 7.05 20.70 193.62a 8.80 -57.49a 9.10 3.41

Mean 6.58 9.40 42.19b 8.13 3.14 7.15 -9.78


AL31 6.20 0.00 8.20 32.26 8.20 0.00

RD32 10.50 54.41 2.70 -74.29a 5.60 107.41a

JS33 10.30 -6.36 7.70 -25.24 11.80 53.25

AA34 3.40 47.83 5.20 52.94 5.40 3.85

JW35 3.9 -48.00a 14 258.97a 6.9 -50.71a

BS37 8.30 -8.79 6.30 -24.10 8.70 38.10

Mean 7.10 6.51 7.35 36.76b 7.77 25.31






Table 6.3


change from previous time point for NSCLC patients receiving twice weekly CA4P

and RT (UKR104 cohort 7).

213


2

4

6

8

10

12

14

16

18

20

22

Blo

od V

olum

e (m

L/10

0mL)

Time points

FR03 CM04 RM05 SF06 HC07 CY09 AI10 SD12 Mean

Figure 6.3

Graph of median whole tumour blood volume for NSCLC patients receiving single

dose or weekly CA4P and RT (Cohorts 1 + 2), plotted at the following time points:


hours after the first dose of CA4P; 4# RT- 1 hour after fourth fraction of

radiotherapy; CA4P2 – 4 hours after the second dose of CA4P; 6# RT- 1 hour after

sixth fraction of radiotherapy; CA4P3 – 4 hours after the third dose of CA4P.

214

MB 2# RT change (%) CA4P1 change (%)

FR03 4.79 7.50 56.58 5.67 18.37

CM04 8.79 7.47 -15.02 8.50 -3.30

RM05 4.34 4.29 -1.15 4.47 3.00

SF06 8.02 9.16 14.29 6.83 -14.78

HC07 6.76 8.53 26.18 6.93 2.51

CY09 7.67 8.81 14.86 7.38 -3.78

AI10 5.89 6.66 13.17 5.59 -5.01

SD12 8.02 7.57 -5.55 4.80 -40.11

Mean 6.78 7.50 12.92 6.27 -5.39

4# RT change (%) CA4P2 change (%) 6# RT change (%) CA4P3 change (%)

HC07 6.15 -9.02 5.62 -16.86 3.59 -46.89a 3.81 -43.64

CY09 7.05 -8.08 5.96 -22.29 6.83 -10.95 5.13 -33.12

AI10 6.56 11.47 6.15 4.50 6.92 17.59 5.74 -2.46

SD12 8.66 8.05 8.30 3.56 7.31 -8.80 7.83 -2.31

Mean 7.11 0.60 6.51 -7.77 6.16 -12.26 5.63 -20.38






Table 6.4


change from mean baseline for NSCLC patients receiving single dose and weekly

CA4P and RT (UKR104 cohorts1+2).

215


FR03 4.79 7.50 56.58 5.67 -24.40

CM04 8.79 7.47 -15.02 8.50 13.79

RM05 4.34 4.29 -1.15 4.47 4.20

SF06 8.02 9.16 14.29 6.83 -25.44

HC07 6.76 8.53 26.18 6.93 -18.76

CY09 7.67 8.81 14.86 7.38 -16.23

AI10 5.89 6.66 13.17 5.59 -16.07

SD12 8.02 7.57 -5.55 4.80 -36.59

Mean 6.78 7.50 12.92 6.27 -14.94


HC07 6.15 -11.26 5.62 -8.62 3.59 -36.12 3.81 6.13

CY09 7.05 -4.47 5.96 -15.46 6.83 14.60 5.13 -24.89

AI10 6.56 17.35 6.15 -6.25 6.92 12.52 5.74 -17.05

SD12 8.66 80.42 8.30 -4.16 7.31 -11.93 7.83 7.11

Mean 7.11 20.51 6.51 -8.62 6.16 -5.23 5.63 -7.18






Table 6.5


change from previous time point for NSCLC patients receiving single dose and

weekly CA4P and RT (UKR104 cohorts1+2).

216


2

4

6

8

10

12

14

16

18

20

22

24

Perm

eabi

lity

surfa

ce a

rea

prod

uct

(ml/1

00m

l/min

)

Time points

AL31 RD32 JS33 AA34 JW35 BS37 Mean

Figure 6.4

Graph of median whole tumour permeability surface area product for NSCLC

patients receiving twice weekly CA4P and RT (Cohort 7), plotted at the following

time points: MB- mean baseline; 2# RT- 1 hour after second fraction of radiotherapy;

CA4P2 – 4 hours after the second dose of CA4P; 4# RT- 1 hour after fourth fraction

of radiotherapy; CA4P4 – 4 hours after the fourth dose of CA4P; 6# RT- 1 hour after


217


AL31 18.25 16.50 -9.59 14.00 -23.29 15.00 -17.81

RD32 9.00 9.00 0.00 13.50 50.00a 9.00 0.00

JS33 15.00 17.00 13.33 15.50 3.33 21.00 40.00a

AA34 7.25 8.00 10.34 7.00 -3.45 8.00 10.34

JW35 14.25 18.50 29.82 14.50 1.75 19.00 33.33

BS37 11.25 20.00 77.78a 14.00 24.44 11.50 2.22

Mean 12.50 14.83 20.28b 13.08 8.80 13.92 11.35


AL31 13.50 -26.03a 11.00 -39.73a 14.50 -20.55

RD32 9.00 0.00 8.00 -11.11 9.50 5.56

JS33 18.50 23.33 17.50 16.67 18.50 23.33

AA34 8.50 17.24 10.00 37.93a 10.00 37.93a

JW35 22.00 54.39a 16.00 12.28 16.00 12.28

BS37 13.50 20.00 13.50 20.00 14.50 28.89

Mean 14.17 14.82b 12.67 6.01 13.83 14.57b

aSignificant individual change in PS bSignificant group change in PS





Table 6.6

DCE-CT derived permeability surface area product (PS) values (ml/100ml/min) and

percentage change from mean baseline for NSCLC patients receiving twice weekly

CA4P and RT (UKR104 cohort 7).

218


AL31 18.25 16.50 -9.59 14.00 -15.15 15.00 7.14

RD32 9.00 9.00 0.00 13.50 50.00a 9.00 -33.33a

JS33 15.00 17.00 13.33 15.50 -8.82 21.00 35.48a

AA34 7.25 8.00 10.34 7.00 -12.50 8.00 14.29

JW35 14.25 18.50 29.82 14.50 -21.62 19.00 31.03

BS37 11.25 20.00 77.78a 14.00 -30.00a 11.50 -17.86

Mean 12.50 14.83 20.28b 13.08 -6.35 13.92 6.13


AL31 13.50 -10.00 11.00 -18.52 14.50 31.82

RD32 9.00 0.00 8.00 -11.11 9.50 18.75

JS33 18.50 -11.90 17.50 -5.41 18.50 5.71

AA34 8.50 6.25 10.00 17.65 10.00 0.00

JW35 22.00 15.79 16.00 -27.27a 16.00 0.00

BS37 13.50 17.39 13.50 0.00 14.50 7.41

Mean 14.17 2.92 12.67 -7.44 13.83 10.61






Table 6.7


percentage change from previous time point for NSCLC patients receiving twice

weekly CA4P and RT (UKR104 cohort 7).

219


2

4

6

8

10

12

14

16

18

20

22

24

Per

mea

bilit

y su

rface

are

a pr

oduc

t (m

l/100

ml/m

in)

Time points

FR03 CM04 RM05 SF06 HC07 CY09 AI10 SD12 Mean

Figure 6.5

Graph of median whole tumour permeability surface area product for NSCLC

patients receiving single or weekly CA4P and RT (Cohorts 1 + 2), plotted at the

following time points: MB- mean baseline; 2# RT- 1 hour after second fraction of

radiotherapy; CA4P1 – 4 hours after the first dose of CA4P; 4# RT- 1 hour after

fourth fraction of radiotherapy; CA4P2 – 4 hours after the second dose of CA4P; 6#

RT- 1 hour after sixth fraction of radiotherapy; CA4P3 – 4 hours after the third dose

of CA4P.

220


FR03 9.25 13.44 45.30a 9.22 -0.32

CM04 16.60 12.56 -24.34 14.59 -12.11

RM05 12.58 12.46 -0.91 13.59 8.07

SF06 12.13 16.90 39.38a 21.11 74.10a

HC07 9.23 10.33 11.98 10.41 12.85

CY09 11.68 13.67 17.09 11.91 2.01

AI10 9.97 11.50 15.35 9.18 -7.92

SD12 11.75 13.23 12.60 7.65 -34.89a

Mean 11.65 13.01 14.55b 12.21 5.22


HC07 11.13 20.65 10.34 12.09 7.25 -21.41 7.99 -13.39

CY09 13.92 19.23 18.09 54.95 16.33 39.87 17.05 46.04

AI10 9.35 -6.22 10.38 4.11 10.54 5.72 12.82 28.59

SD12 11.46 -2.47 13.14 11.83 15.61 32.85 15.22 29.53

Mean 11.47 7.80 12.99 20.74 12.43 14.26 13.27 22.69






Table 6.8


percentage change from mean baseline for NSCLC patients receiving single dose

and weekly CA4P and RT (UKR104 cohorts1+2).

221


FR03 9.25 13.44 45.30a 9.22 -31.40a

CM04 16.60 12.56 -24.34 14.59 16.16

RM05 12.58 12.46 -0.91 13.59 9.07

SF06 12.13 16.90 39.38a 21.11 24.91

HC07 9.23 10.33 11.98 10.41 0.77

CY09 11.68 13.67 17.09 11.91 -12.87

AI10 9.97 11.50 15.35 9.18 -20.17

SD12 11.75 13.23 12.60 7.65 -42.18a

Mean 11.65 13.01 14.55b 12.21 -6.96


HC07 11.13 6.92 10.34 -7.10 7.25 -29.88a 7.99 10.21

CY09 13.92 16.88 18.09 29.96 16.33 -9.73 17.05 4.41

AI10 9.35 1.85 10.38 11.02 10.54 1.54 12.82 21.63

SD12 11.46 49.80a 13.14 14.66 15.61 18.80 15.22 -2.50

Mean 11.47 18.86b 12.99 12.13 12.43 -4.82 13.27 8.44






Table 6.9


percentage change from previous time point for NSCLC patients receiving single

dose and weekly CA4P and RT (UKR104 cohorts1+2).

222

CHAPTER 7

Tumour vascular effects of combined vascular

disruption, EGFR inhibition and radiation in

Head and Neck cancer.

7.1 Aims

To determine tumour vascular effects, using single level perfusion CT in

Head and Neck squamous cell carcinoma, of radical radiotherapy in

combination with weekly combretastatin A-4 phosphate and cetuximab.

To detect changes in cytokine production and blood composition in patients

with Head and Neck squamous cell carcinoma receiving radical radiotherapy

in combination with weekly combretastatin A-4 phosphate and cetuximab.

7.2 Introduction

This chapter contains details of clinical experiments using DCE-CT to assess the

tumour vascular changes resulting from the administration of the VDA CA4P, in

addition to radiotherapy and the EGFR inhibitor, cetuximab, in patients with SCCs of

the head and neck region.

In the treatment of locally advanced SCC of the head & neck, radiotherapy is

commonly employed, either preoperatively or postoperatively. Whilst

hyperfractionated and accelerated regimens have been extensively studied, the

223

standard fractionation used in the UK is 2Gy per fraction for 6.5 to 7 weeks.

However, radiotherapy alone is no longer the standard of care for the treatment of

this patient group. A large meta-analysis, using individual patient data, most recently

updated in 2009, examining the use of cisplatin-based chemotherapy in head and

neck cancer has shown a more pronounced benefit with concomitant chemotherapy

compared to induction chemotherapy, producing a hazard ratio of death of 0.81

(p<0.0001) and an absolute benefit 6.5% at 5 years (Pignon et al., 2009).

Concomitant cetuximab has also been shown to improve outcome in locally

advanced head and neck cancer, producing a median overall survival of 49 months

compared to 29.3 months for radiotherapy alone; hazard ratio of 0.74 (p=0.03)

(Bonner et al., 2006).

As previously discussed in Chapter 4, there have been preclinical studies that have

demonstrated enhanced anti-tumour effects with the addition of a VDA to combined

radiotherapy and EGFR inhibition ([Bozec et al., 2006], [Raben et al., 2004]). In the

experiments described in Chapter 4, using the head and neck squamous cell

carcinoma (HNSCC) tumour model FaDu, enhanced anti-tumour effect was

observed with cetuximab, CA4P and radiotherapy; this combination being the only

treatment to produce significant tumour growth delay compared to radiation alone.

As part of a phase Ib study, we undertook to determine whether this triple

combination was tolerable in the clinical setting and to explore the resultant effects

on the tumour vasculature, using DCE-CT imaging and circulatory biomarkers.

224

7.3 Methods

7.3.1 Patient selection and recruitment

All patients were recruited as part of the study entitled “Phase Ib trial of CA4P

(combretastatin A-4 phosphate) in combination with radiotherapy in patients with

advanced cancer of the lung, head & neck or prostate: CA4P protocol number

UKR104”. The full inclusion and exclusion criteria in the UKR-104 protocol for all

cohorts receiving treatment with radiotherapy and CA4P are listed in Appendix B.

The analysis of one cohort of this phase 1b clinical trial is examined in this chapter,

the treatment scheduling of which is shown in Table 2.1. It was intended that 6

patients would be treated in each of the treatment cohorts, provided the combination

treatment was well tolerated and no dose limiting toxicities (DLTs) were observed.

The stopping criteria were defined as 2 patients in a single cohort experiencing

DLTs.

Patients with histologically confirmed squamous cell carcinoma of the head and

neck, suitable for radical treatment, were prospectively recruited; fulfilling the criteria

for inclusion in the study, they proceeded to receive radical radiotherapy to the head

and neck, 64 to 70Gy in 32 to 35 fractions over 6.5 to 7 weeks (as per section

2.2.1.2). This was delivered in combination with CA4P (as per section 2.2.2),

50mg/m2 i.v. after the final fraction of radiotherapy each week; it was intended that

each patient was to receive a total of 7 doses of CA4P. Concurrent cetuximab was

also delivered, as per section 2.2.3, with a loading dose given one week prior to

radiotherapy and further doses given weekly for the duration of radiotherapy.

7.3.2 Imaging

Single level DCE-CT was used to assess changes in tumour vascularity, resulting

from these combination therapies, using the technique described in section 2.3.1.

225

Up to 9 DCE-CT scans were performed at the following time points: 2 baseline

pretreatment scans; 4 to 6 days after loading dose of cetuximab on the day of but

prior to first fraction of radiotherapy; 1 hour after the final fraction of radiotherapy in

the first week (1 hour prior to administration of CA4P), 4 hours after the first dose of

CA4P and 72 hours after the first dose of CA4P; 1 hour after the final fraction of

radiotherapy in week 5 (1 hour prior to administration of CA4P), with further CTs at 4

hours and 72 hours after the subsequent dose of CA4P.

7.3.3 Blood sampling

Following the insertion of a cannula, into a suitable forearm vein, 10 mls of blood

was collected in EDTA tubes for full blood count and to provide plasma samples for

ELISA (as per section 2.4). Blood samples were taken at four designated time points

with the first dose of CA4P administered: preCA4P, 4 hours post CA4P, 6 to 8 hours

post CA4P and 1 week post CA4P.

7.3.4 Statistical analysis

Statistical comparison of changes in blood count and cytokine parameters, between

time points, were assessed using a paired samples t-test, as per section 2.6.4.

7.4 Results

7.4.1 Head and Neck Single Level DCE- CT

Four patients were treated in this cohort, 3 males and 1 female, mean age 73 years

(range 65 to 86 years). DLTs of myocardial ischaemia were observed in the third

and fourth patients treated, after the third and fourth doses of CA4P respectively,

which fulfilled the stopping criteria for the cohort, therefore no further patients were

treated. Only the first patient in the cohort received the intended 7 doses of CA4P,

226

the third and fourth patients only receiving 3 and 4 doses respectively. These three

patients completed the planned radiotherapy and cetuximab treatment. The second

treated patient developed aspiration pneumonia, attributed to his radical

radiotherapy, and whilst an inpatient with this problem, he experienced a fall,

resulting in a fractured neck of femur. As a result of these complications the second

patient received only 4 doses of CA4P (on weeks 1,2,3 and 5) and did not complete

the intended radiotherapy or cetuximab treatments.

There were 21 studies for analysis from 3 patients (6 studies each for the first and

third patients and 9 studies for the second patient). The final three DCE-CT scans

for the first patient were performed in the final week of the radiotherapy treatment,

when it was noted that due to the complete response of his primary tumour no

further measurements could be taken. Subsequently, there was rescheduling of the

final 3 scans for the following patients in the cohort, initiating them at the end of the

fifth week of radiotherapy. For the second patient the DCE-CT scans were

undertaken as per the new schedule but the final scans were performed at the end

of the fifth week with the fourth dose of CA4P, as the patient had missed one dose

of CA4P in the previous week. The third patient did not have scans in the fifth week

as the CA4P had been discontinued; due to the previously stated observed toxicity.

The final patient in the cohort received her treatment as an adjuvant, with no

residual macroscopic disease and was therefore not suitable for DCE-CT

assessment of response. An example of the colour DCE-CT parametric maps for 1

patient is shown in Figure 7.1.

Due to only 3 patients having DCE-CT scanning, it was not possible to use

reproducibility statistics to reliably ascertain the significances of any changes seen

in the DCE-CT parameters. Descriptive analysis of the observed changes was

227

therefore undertaken. The changes in all parameters measured for the group mean

and individual patients are summarised on Table 7.1.

7.4.2 Blood Volume

The median blood volume (BV) results for the 3 patients and the mean values for

the cohort, at each of the time points where DCE-CT was performed, are shown in

Tables 7.2 and 7.3. These results were then plotted to produce the graph seen in

Figure 7.2.

No real change of any magnitude was seen in median tumour BV at 4 to 5 days

after the loading dose of cetuximab (Cet) or 1 hour after the fifth fraction of

radiotherapy (5#RT). A variable response was observed at 4 hours after the first

dose of CA4P; patient JC36 had an individual increase of 84%, compared to mean

baseline, and of 123.7%, compared to after the fifth fraction of radiotherapy,

whereas the other 2 patients had decreases of –40.8% and –28.0% compared to

mean baseline. Patient HC38 had an increase in BV of 127.9% at 72 hours after the

first dose of CA4P (CA4P1), compared to 4 hours after the same dose of CA4P,

although again JC36 showed changes in the other direction with a decrease of –

47.5%. HC38 had a further large increase of 95.2% at 1 hour after the twenty-fifth

fraction of radiotherapy (25#RT), compared to mean baseline.

7.4.3 Permeability surface area product

The median permeability surface area product (PS) results for the 3 patients and the

mean values for the cohort, at each of the time points where DCE-CT was

performed, are shown in Tables 7.4 and 7.5. These results were then plotted to

produce the graph seen in Figure 7.3.

228

At 4 to 5 days after the loading dose of cetuximab (Cet) and prior to the first fraction

of radiotherapy, a reduction in group mean PS was produced of -10.2%, compared

to mean baseline (MB). At this time point, patient GK39 had an individual decrease

in PS of -40.0%, patient HC38 had a decrease of lesser magnitude and patient JC36

actually had an increase of 19.7%, all compared to mean baseline. After the fifth

fraction of radiotherapy (5#RT) there was a 20.3% increase in the group mean PS,

compared to the previous time point (after the loading dose of cetuximab), with an

increase of 42.3% seen with patient JC36 and of 25.0% with patient HC38. As seen

before, a variation in response was observed; GK39 having a decrease of –43.9%,

compared to patient JC36 who had an increase of 70.3%, both compared to mean

baseline.

Four hours after the first dose of CA4P (CA4P1), patient JC36 had an individual

increase in PS of 110% compared to mean baseline and 20% compared to 1 hour

after the fifth fraction of radiotherapy. Although this remained raised at 72 hours

after the first dose of CA4P and prior to the sixth fraction of radiotherapy (72h 1),

compared to mean baseline (104.4%), there was, in fact, a small decrease

compared to the previous time point. There were small increases in the group mean

PS at 4 hours (16.0%) and 72 hours (18.7%) after the first dose of CA4P. At these

two time points patient GK39 had individual decreases in permeability surface area

product; at 4 hours after CA4P a decrease of -57.6% compared to mean baseline

and a decrease of –24.5% compared to 1 hour after the fifth fraction of radiotherapy,

and then at 72 hours a decrease of –51.9% compared to mean baseline.

At 1 hour after the twenty-fifth fraction of radiotherapy (25#RT) for patient HC38,

there was an increase in PS compared to both mean baseline (25.3%) and 72 hours

after the first dose of CA4P (21%). There were further individual increases for this

patient at 4 hours after the fourth dose of CA4P of 55.3 % compared with mean

229

baseline and 24.0% compared with 1 hour after the twenty-fifth fraction of

radiotherapy. Finally, at 72 hours after the fourth dose of CA4P, PS increased

further to 82.15ml/100ml; a relatively large increase compared to mean baseline

(75.6%), but no real change compared with the previous time point, 4 hours after the

fourth dose of CA4P.

7.4.4 Blood Flow

The median blood flow (BF) results for the 3 patients and the mean values for the

cohort, at each of the time points where DCE-CT was performed, are shown in

Tables 7.6 and 7.7. These results were then plotted to produce the graph seen in

Figure 7.4.

At 4 to 6 days after administration of the loading dose of cetuximab (Cet), patient

GK39 demonstrated an individual increase in BF of 169.3% compared with mean

baseline (MB). Despite no sizable changes observed with the 2 other patients, a

group mean increase of 48.5% was still produced. After the fifth fraction of

radiotherapy (5#RT), despite a slight reduction in blood flow for patient GK39

compared with the previous time point, there was an individual increase for this

patient (131.3%) and a group mean increase (55.1%) in blood flow compared to

mean baseline. At four hours after the first dose of CA4P, there were comparatively

large individual reductions in BF compared with 1 hour after the fifth fraction of

radiotherapy seen for 2 patients: patient HC38 (-57.1%) and patient GK39 (-63.5%).

This reduction in BF was not seen for all patients at this time point, with patient JC36

having a significant individual increase compared with 1 hour after the fifth fraction

of radiotherapy (95.5%) and mean baseline (91.7%). Following this, the individual

increase in BF of greatest magnitude observed in this study was patient HC38 at 4

hours after the fourth dose of CA4P, compared with 1 hour after the twenty-fifth

230

fraction of radiotherapy, with an increase of 87.2%. No other large individual or

group changes in BF were observed.

7.4.5 Blood Testing

All four patients in cohort 6 underwent blood testing. Blood samples for first patient,

JC36, were delayed and collected with the sixth dose of CA4P. The final three

patients treated in the cohort all had sampling as planned, with the first dose of

CA4P.

7.4.6 Full Blood Count

The results from the full blood count testing, undertaken for all four head and neck

patients are shown in Table 7.8. The results for white cell count, neutrophil count,

lymphocyte count and monocyte count, including the mean values, were then

plotted to produce the graphs seen in Figures 7.5, 7.6, 7.7 and 7.8 respectively.

All four patients demonstrated significant increases at 6 hours, compared to pre

CA4P, in total white blood cells with a mean increase of 3.45 (p=0.0151), and

neutrophils with a mean increase of 3.8 (p=0.0152). This compared to 4 hours after

CA4P, when although there was an increase in the mean white cell and neutrophil

counts, 2 patients (HC38 and GK39) in fact had a decrease in both of these

parameters and these mean increases were not significant on paired t-testing

(Figures 7.5 and 7.6). At 1 week post CA4P, both the white cell and neutrophil

counts had decreased significantly compared with 6 to 8 hours after CA4P, with

mean decreases of 4.5 (p=0.0031) and 4.6 (p=0.0033) respectively. There were no

other significant decreases in these parameters between the various time points

when samples were collected.

231

A significant reduction in lymphocyte count was seen at 4 hours after CA4P

compared to preCA4P (Figure 7.7); a mean reduction of 0.275 (p=0.0222). At 4

hours after CA4P all four patients had a decrease in lymphocyte count. There was a

further reduction in the lymphocyte count for patient GK39 but an increase for JC36,

between 4 hours and 6 to 8 hours, returning to the same level as preCA4P. The

lymphocyte counts for the other 2 patients between these time points were

unchanged and paired t-testing at 6 to 8 hours compared to preCA4P revealed only

a non-significant trend towards a sustained decrease at 6 to 8 hours (p=0.0632).

The monocyte count also significantly changed following administration of CA4P

with a mean increase of 0.25 (p=0.0154) between 4 hours and 6 to 8 hours after

CA4P; this rise being produced in all four patients (Figure 7.8). At 4 hours after

CA4P compared to preCA4P, a mean decrease of -0.3 was produced, with 3

patients having a decrease in monocyte count, although patient JC36 had a small

increase, which was not statistically significant (p=0.1343). The same three patients

had an increase between 4 hours and 1 week after CA4P, but, once again, their

response differed from patient JC36, who had no change in the monocyte count

between these time points, producing a mean increase of 0.25; a non-significant

trend towards a sustained increase in monocyte count at 1 week (p=0.0632). No

other significant changes in blood parameters, including basophils and eosinophils

(data not shown in tables), were seen over the study time period.

7.4.7 ELISA

The results from the ELISA testing for the cytokines VEGF, VEGFR-1, G-CSF and

SDF-1 are shown in Table 7.9. These results, including the mean values, were then

plotted for each of the cytokines, to produce the graphs seen in Figures 7.9, 7.10,

7.11 and 7.12 respectively.

232

A mean increase in VEGF between preCA4P and 4 hours after CA4P of 44 pg/ml

(p=0.1203) was produced; 3 patients showing an increase and patient HC38

showing no change (Figure 7.9). Between 4 hours and 6 to 8 hours after CA4P, a

decrease in the mean by 24.75 pg/ml (p=0.0679) was produced; the only patient to

show no decrease was HC38. By 1 week, the mean VEGF had increased by 16

pg/ml compared to 6 to 8 hours after CA4P, with patient GK39 having a decrease,

although this was not significant. The variability of response between the time points

seen with VEGF was not observed with VEGFR1, where all 4 patients had a similar

direction of change throughout the study period, except between 4 and 6 to 8 hours

after CA4P, where patient JC36 had a decrease in VEGFR1, whereas the other 3

showed rises (Figure 7.10). A highly significant mean increase was observed in

VEGFR1 at 4 hours, compared to preCA4P, of 67.5 pg/ml (p=0.0108). At 6 to 8

hours, a mean increase of 96.75 pg/ml (p=0.065), compared to preCA4P, was

produced but this was not significant. There was a mean increase in VEGFR1 of

29.25 pg/ml between 4 and 6 to 8 hours after CA4P, but this was also not

significant. Significant decreases were seen at 1 week, compared to both 4 hours

and 6 to 8 hours after CA4P, with mean decreases of 88.5 pg/ml (p=0.0252) and

117.75 pg/ml (p=0.0061) respectively.

The G-CSF results show a similar pattern of change, in mean concentration, to

VEGFR1 (Figure 7.11). There was an increase in mean at 4 hours, further increase

at 6 hours and a decrease at 1 week. These changes in direction of results were

consistent for the same three patients at each time point but patient JC36 had

changes in the opposite direction for each one. As a result, none of these changes

were significant on paired t-testing. There were also no significant changes in SDF-1

between the tested time points (Figure 7.12). The validity of the SDF-1 results are

uncertain, as, after analysis had been undertaken, it came to light that a further

centrifugation step of 10000g for 10 minutes should have been performed. This was

233

required to remove platelets as they express a receptor for SDF-1 and this may

affect the results of the assay.

7.5 Discussion

The scheduling of CA4P in this chapter was the final escalation of weekly CA4P

dose intensity in the UKR104 study. Of the seven treatment cohorts in the study, 4

were delivered using radical radiotherapy with a once daily fractionation, 5 fractions

per week. Previous prostate cohorts had received CA4P 50mg/m2, either as a single

dose or weekly for 4 weeks, with the final cohort receiving 63mg/m2, also weekly for

4 weeks. CA4P was delivered after the final fraction of each week, to allow a

recovery time of at least 72 hours, prior to recommencement of radiotherapy the

next week. The radical fractionation used in cohort 6 for the treatment of SCC of the

head & neck was delivered over 6.5 to 7 weeks, which allowed escalation of

concurrent CA4P, with patients scheduled to receive 7 weekly doses at 50mg/m2.

Concomitant cetuximab was incorporated into the treatment schedule for cohort 6,

as a result of treatment with radiotherapy alone being superseded by combination

therapies. This monoclonal antibody targets EGFR, inhibiting cellular processes,

including proliferation, but also indirectly inhibits angiogenesis. It has been

demonstrated to reduce expression of the pro-angiogenic factors VEGF, IL-8 and

bFGF ([Petit et al., 1997], [Perrotte et al., 1999]). By combining one of the current

standards of care, (cetuximab and radiotherapy), with CA4P, a vascular disruptive

agent directed at a different target and with a different set of documented side

effects, this treatment was designed to incorporate both vascular disruptive and

antiangiogenic strategies. To determine the vascular effects resulting from this

treatment single level DCE-CT, blood count and cytokine parameters were

examined. Single level DCE-CT was selected to monitor the vascular changes in

234

this cohort, taking into account the relative size of the primary tumours to be

assessed and also to allow assessment of blood flow. This gave z-axis coverage, for

the CT scanner with four detectors, of approximately 2cm. From the 3 patients

assessed, no consistent trends in any of the DCE-CT parameters measured were

seen, but large changes were detected both between time points and in comparison

with baseline values.

From Figure 7.2 the rapid increase in blood volume at 72h after the first dose of

CA4P with patient HC38 is evident, in comparison to the low level at 4 hours post

dose, with the blood volume increasing to a peak after the 25th fraction of

radiotherapy. Decreases in blood volume, after the first and fourth doses of CA4P,

were also seen with this patient. The use of DCE-CT allowed the identification of a

reduction in the group mean PS, compared to mean baseline 4 to 5 days after the

loading dose of cetuximab, followed by an increase after the fifth fraction of

radiotherapy. The mean PS remained raised at 4 hours and 72 hours after the first

dose of CA4P, with only changes of small magnitude between time points. However,

at every time point, up to 72 hours after the first dose of CA4P, there were individual

changes in the other direction to that seen with the group mean. Patient HC38 had

no sizable individual change in PS until after the twenty-fifth fraction of radiotherapy,

when there was a greater increase that persisted at 4 hours and 72 hours after the

fourth dose of CA4P (Figure 7.3). For this patient, the cumulative effect of this

combination treatment increased the tumour PS and resulted in no acute reduction

in PS at four hours after the fourth dose of CA4P, compared to that seen after the

first dose of CA4P.

Discernible changes in BF also resulted from the combination of therapies, with a

large rise in BF seen after the loading dose of cetuximab for patient GK39, which

resulted in a large increase in the group mean, despite the other 2 patients showing

235

only small decreases in BF. The group mean increase at 1 hour after the fifth

fraction of radiotherapy was mainly due to the magnitude of increase of BF observed

with patient GK, compared to mean baseline, when there had, in fact, been a small

reduction in blood flow for this patient between 4 to 5 days after the loading dose of

cetuximab and the fifth fraction of radiotherapy. The BF for the other 2 patients at

this time point both increased, showing a further variable response. The expected

reduction in blood flow 4 hours after CA4P was observed, with large reductions for

patient HC38 and patient GK39, but in keeping with the variability previously

observed, patient JC36 had a large increase at this time point.

There is an ongoing quest to identify circulatory biomarkers that may be easily

extracted by relatively non-invasive diagnostic techniques, including circulating

levels of endothelial progenitor cells (EPC), pro-angiogenic cytokines and receptors,

and these are now being incorporated into early phase clinical trials of vascular

directed therapies ([Shaked et al., 2006], [Bertolini et al., 2006], [Shaked et al.,

2009], [Vermeulen et al., 2002.], [Lowndes et al., 2008], [Zhu et al., 2009]). EPCs

from the bone marrow are recruited to tumour sites by a number of chemokines,

including VEGF, SDF-1 and angiopoietin ([Hattori et al., 2001], [Peichev et al.,

2000]). SDF-1 acts by binding to CXCR4 on circulating vasculogenic stem cells and

facilitates their adhesion, migration and homing to the tumour microenvironment

([Ceradini et al., 2004], [Burger and Kipps, 2006], [Folkins et al., 2009]). This

interaction between SDF-1 and CXCR4 is not limited to vasculogenic stem cells,

with similar effects described in both cancer stem cells and normal stem cells,

including the mobilisation of polymorphonuclear neutrophils and haemopoietic

progenitor cells from the bone marrow ([Kucia et al., 2005], [Pelus et al., 2005]).

In this chapter, patients being treated with radical radiotherapy and cetuximab for

SCCs of the head & neck, had significant increases in both neutrophil count (at 6 to

236

8 hours) and VEGFR1 (at 4 hours) after receiving CA4P, demonstrating the acute

vasculogenic response resulting from the CA4P-induced damage to the tumour

vasculature. In keeping with this, the graphs for neutrophils, VEGFR1 and G-CSF

(Figures 7.6, 7.10 and 7.11) all show a similar shape in their mean curves and the

mean curve for VEGF demonstrates an increase at 4 hours prior to a reduction at 6

to 8 hours. All three parameters demonstrate a statistically significant decrease,

returning to baseline, when assessed at 1 week after receiving CA4P.

The changes seen for VEGF and G-CSF were often consistent for 3 patients, but

due to the small numbers in the cohort, 100% of changes had to be in the same

direction to achieve significance. The standard full blood count testing was sensitive

enough to demonstrate these significant changes in neutrophil count, also reflected

in the white cell count results. It was not possible to test for EPCs at the local

hospital laboratory. Whether the significant reduction in lymphocyte count at 4 hours

is related to this vasculogenic response is uncertain, but lymphopenia is a

documented side effect of CA4P. It could also be due to a direct toxic effect or a

sensitivity of the lymphocytes to the effects of CA4P.

By using both imaging and circulatory biomarkers, this enabled confirmation of the

varied responses seen between the different patients. At 4 hours post CA4P, patient

JC36 had documented rises in tumour BV, PS and BF, and rises in neutrophil count,

VEGF and VEGFR, which peaked at 4 hours. In addition, the concentration of GCSF

had decreased; with a further reduction at 6 to 8 hours post CA4P. These findings

contrast with patient HC38, who had decreases in tumour BV, PS and BF, plus

decreased neutrophil count, increasing VEGFR and increasing GCSF; these three

circulatory parameters then continued to increase, peaking at 6 to 8 hours. These

differences in patient HC38, may have resulted from a less well vascularised and

more necrotic tumour, which would, therefore, be more reliant on the vessels

237

238

damaged by CA4P. A prolongation of the vasculogenic response, as seen with the

further increases in neutrophil count and VEFR at 6 to 8 hours, may result from this

increased vascular and tumour damage.

7.6 Conclusion

The experiments in this chapter have demonstrated that single level DCE-CT

parameters can be used to detect acute changes in the vasculature of SCCs of the

head & neck, undergoing treatment with radiotherapy, cetuximab and CA4P.

However, a marked heterogeneity in the DCE-CT parameters was demonstrated,

which may represent the inherent heterogeneity of the tumours. In this experiment,

we have also harnessed the use of specific circulatory biomarkers and have

demonstrated significant vasculogenic responses to CA4P- induced vascular

damage; with significant acute rises in neutrophil count and VEGFR1. This indicates

that the indirect antiangiogenic action of cetuximab does not prevent this

vasculogenic response, in patients with SCC of the head & neck who are receiving

radical radiotherapy, cetuximab and CA4P.

The findings from this study were limited by the observed toxicity of increased

myocardial ischaemia with these combined therapies. Prior to the combination being

looked at again in the clinical setting, further preclinical studies are required to

determine whether the detrimental normal tissue cardiovascular effects, produced

by the combination of CA4P and cetuximab, can be modulated by anti-hypertensive

therapies or other agents, without the loss of the combined antitumour effects.

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MB Cet change (%) 5#RT change (%) CA4P1 change (%) 72h 1 change (%)

Mean BV 62.69 57.38 -7.17 59.16 0.17 71.04 20.54 66.57 24.84

Mean PS 36.14 31.35 -10.19 38.65b 20.30 37.68 -5.41 39.19 6.57

Mean BF 47.60 52.99 48.45 63.34 16.68 54.20 -8.40 55.97 29.80


JC36 BV 77.90 66.45 -14.70 64.05 -3.61 143.30a 123.73 75.20a -47.52

JC36 PS 25.28 30.25 19.68 43.05a 42.31 53.25a 23.69 51.65 -3.00

JC36 BF 55.98 45.80a -18.18 54.90 19.87 107.30a 95.45 72.95a -32.01


HC38 BV 74.22 70.30 -5.28 82.93 17.97 43.93 -47.03 100.10a 127.85

HC38 PS 46.78 42.00 -10.22 52.50a 25.00 44.40a -15.43 48.43 9.08

HC38 BF 68.93 64.97 -5.75 93.73 44.28 40.20a -57.11 74.37a 84.99


GK39 BV 35.95 35.40 -1.53 30.50 -13.84 25.90 -15.08 24.40 -5.79

GK39 PS 36.35 21.80a -40.03 20.40 -6.42 15.40 -24.51 17.50 13.64

GK39 BF 17.90 48.2a 169.27 41.4 -14.11 15.10a -63.53 20.60 36.42

aIndividual change in BV/ PS/ BF >2x mean difference between 2 baseline scans

bGroup change in BV/ PS/ BF >2x mean difference between 2 baseline scans

MB- mean baseline; Cet- 4 to 6 days after first dose of cetuximab and prior to the first

fraction of radiotherapy; 5# RT- 1 hour after fifth fraction of radiotherapy; CA4P1 – 4 hours

after the first dose of CA4P; 72h 1- 72 hours after the first dose of CA4P

Table 7.1 DCE-CT derived median blood volume (BV) values (ml/100ml), median permeability

surface area product (PS) values (ml/100ml/min) and median Blood Flow (BF)

values (ml/100ml/min), together with percentage change from previous time point,

for each patient and group mean (UKR104 cohort 6).

240

MB Cet 5#RT CA4P1 72h1 25#RT CA4P4 72h40

20

40

60

80

100

120

140

160

Blo

od V

olum

e (m

l/100

ml)

Time points

JC36 HC38 GK39 Mean

Figure 7.2 Graph of median single level tumour blood volume for HNSCC patients receiving

weekly CA4P, weekly cetuximab and RT (Cohort 6), plotted at the following time

points: MB- mean baseline; 2# RT- 1 hour after second fraction of radiotherapy;

CA4P1 – 4 hours after the first dose of CA4P; 72h 4 – 72 hours after the first dose of

CA4P; 25# RT- 1 hour after twenty fifth fraction of radiotherapy; CA4P4 – 4 hours

after the fourth dose of CA4P; 72h 4 – 72 hours after the fourth dose of CA4P.

241


JC36 77.90 66.45 -14.70 64.05 -17.78 143.30a 83.95 75.20 -3.47

HC38 74.22 70.30 -5.28 82.93 11.74 43.93 -40.80 100.10 34.88

GK39 35.95 35.40 -1.53 30.50 -15.16 25.90 -27.96 24.40 -32.13

Mean 62.69 57.38 -7.17 59.16 -7.06 71.04 5.06 66.57 -0.24

25#RT change (%) CA4P4 change (%) 72h 4 change (%)

HC38 144.90a 95.24 107.65 45.05 111.85 50.71

aIndividual change in BV >2x mean difference between 2 baseline scans

bGroup change in BV >2x mean difference between 2 baseline scans



after the first dose of CA4P; 72h 1- 72 hours after the first dose of CA4P; 25# RT- 1 hour

after twenty fifth fraction of radiotherapy; CA4P4 – 4 hours after the fourth dose of CA4P;

72h 4- 72 hours after the fourth dose of CA4P; 6# RT- 1 hour after sixth fraction of

radiotherapy; CA4P4 – 4 hours after the third dose of CA4P.

Table 7.2 DCE-CT derived median blood volume (BV) values (ml/100ml) and percentage

change from mean baseline for patients with SCC Head & Neck receiving weekly

CA4P, cetuximab and RT (UKR104 cohort 6).

242


JC36 77.90 66.45 -14.70 64.05 -3.61 143.30a 123.73 75.20a -47.52

HC38 74.22 70.30 -5.28 82.93 17.97 43.93 -47.03 100.10a 127.85

GK39 35.95 35.40 -1.53 30.50 -13.84 25.90 -15.08 24.40 -5.79

Mean 62.69 57.38 -7.17 59.16 0.17 71.04 20.54 66.57 24.84


HC38 144.90a 44.76 107.65 -25.71 111.85 3.90

aIndividual change in BV >2x mean difference between 2 baseline scans

bGroup change in BV >2x mean difference between 2 baseline scans







Table 7.3 DCE-CT derived median blood volume (BV) values (ml/100ml) and percentage

change from previous time point for patients with SCC Head & Neck receiving

weekly CA4P, cetuximab and RT (UKR104 cohort 6).

243

MB Cetux 5#RT CA4P1 72h1 25#RT CA4P4 72h40

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

Per

mea

bilit

y su

rface

are

a pr

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t (m

l/100

ml/m

in)

Time points

JC36 HC38 GK39 Mean

Figure 7.3

Graph of median single level tumour permeability surface area product for HNSCC

patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6), plotted at the

following time points: MB- mean baseline; 2# RT- 1 hour after second fraction of

radiotherapy; CA4P1 – 4 hours after the first dose of CA4P; 72h 4 – 72 hours after

the first dose of CA4P; 25# RT- 1 hour after twenty fifth fraction of radiotherapy;

CA4P4 – 4 hours after the fourth dose of CA4P; 72h 4 – 72 hours after the fourth

dose of CA4P.

244


JC36 25.28 30.25 19.68 43.05a 70.33 53.25a 110.68a 51.65a 104.35

HC38 46.78 42.00 -10.22 52.50a 12.22 44.40 -5.09 48.43 3.53

GK39 36.35 21.80a -40.03 20.40a -43.88 15.40a -57.63a 17.50a -51.86

Mean 36.14 31.35 -10.19 38.65 12.89 37.68 15.98 39.19 18.67


HC38 58.60a 25.26 72.65a 55.29 82.15a 75.60

aIndividual change in PS >2x mean difference between 2 baseline scans

bGroup change in PS >2x mean difference between 2 baseline scans


fraction of radiotherapy; CA4P1 – 4 hours after the first dose of CA4P; 72h 1- 72 hours after

the first dose of CA4P; 25# RT- 1 hour after twenty fifth fraction of radiotherapy; CA4P4 – 4

hours after the fourth dose of CA4P; 72h 4- 72 hours after the fourth dose of CA4P; 6# RT- 1

hour after sixth fraction of radiotherapy; CA4P3 – 4 hours after the third dose of CA4P.

Table 7.4 DCE-CT derived median permeability surface area product (PS) values

(ml/100ml/min) and percentage change from mean baseline for patients with SCC

Head & Neck receiving weekly CA4P, cetuximab and RT (UKR104 cohort 6).

245


JC36 25.28 30.25 19.68 43.05a 42.31 53.25a 23.69 51.65 -3.00

HC38 46.78 42.00 -10.22 52.50a 25.00 44.40a -15.43 48.43 9.08

GK39 36.35 21.80a -40.03 20.40 -6.42 15.40 -24.51 17.50 13.64

Mean 36.14 31.35 -10.19 38.65b 20.30 37.68 -5.41 39.19 6.57


HC38 58.60a 20.99 72.65a 23.98 82.15a 13.08

aIndividual change in PS >2x mean difference between 2 baseline scans

bGroup change in PS >2x mean difference between 2 baseline scans


fraction of radiotherapy; CA4P1 – 4 hours after the first dose of CA4P; 72h 1- 72 hours after

the first dose of CA4P; 25# RT- 1 hour after twenty fifth fraction of radiotherapy; CA4P4 – 4

hours after the fourth dose of CA4P; 72h 4- 72 hours after the fourth dose of CA4P; 6# RT- 1

hour after sixth fraction of radiotherapy; CA4P3 – 4 hours after the third dose of CA4P.

Table 7.5 DCE-CT derived median permeability surface area product (PS) values

(ml/100ml/min) and percentage change from previous time point for patients with

SCC Head & Neck receiving weekly CA4P, cetuximab and RT (UKR104 cohort 6).

246

MB Cetux 5#RT CA4P1 72h1 25#RT CA4P4 72h40

10

20

30

40

50

60

70

80

90

100

110

120

130

140

Blo

od F

low

Time points

JC HC GK Mean

Figure 7.4

Graph of median single level tumour blood flow for HNSCC patients receiving

weekly CA4P, weekly cetuximab and RT (Cohort 6), plotted at the following time

points: MB- mean baseline; 2# RT- 1 hour after second fraction of radiotherapy;

CA4P1 – 4 hours after the first dose of CA4P; 72h 4 – 72 hours after the first dose of

CA4P; 25# RT- 1 hour after twenty fifth fraction of radiotherapy; CA4P4 – 4 hours

after the fourth dose of CA4P; 72h 4 – 72 hours after the fourth dose of CA4P.

247


JC36 55.98 45.80a -18.18 54.90 -1.92 107.30a 91.69 72.95a 30.33

HC38 68.93 64.97 -5.75 93.73a 35.98 40.20a -41.68 74.37 7.88

GK39 17.90 48.2a 169.27 41.4a 131.28 15.1 -15.64 20.6 15.08

Mean 47.60 52.99 48.45 63.34b 55.11 54.20 11.46 55.97 17.76


HC38 98.80a 43.33 129.05a 87.21 72.70 5.46

aIndividual change in BF >2x mean difference between 2 baseline scans

bGroup change in BF >2x mean difference between 2 baseline scans







Table 7.6 DCE-CT derived median Blood Flow (BF) values (ml/100ml/min) and percentage

change from mean baseline for patients with SCC Head & Neck receiving weekly

CA4P, cetuximab and RT (UKR104 cohort 6).

248


JC36 55.98 45.80a -18.18 54.90 19.87 107.30a 95.45 72.95a -32.01

HC38 68.93 64.97 -5.75 93.73 44.28 40.20a -57.11 74.37a 84.99

GK39 17.90 48.2a 169.27 41.4 -14.11 15.10a -63.53 20.60 36.42

Mean 47.60 52.99 48.45 63.34 16.68 54.20 -8.40 55.97 29.80


HC38 98.80a 32.86 129.05a 30.62 72.70a -43.67

aIndividual change in BF >2x mean difference between 2 baseline scans

bGroup change in BF >2x mean difference between 2 baseline scans

MB- mean baseline Cet- 4 to 6 days after first dose of cetuximab and prior to the first fraction

of radiotherapy; 5# RT- 1 hour after fifth fraction of radiotherapy; CA4P1 – 4 hours after the

first dose of CA4P; 72h 1- 72 hours after the first dose of CA4P; 25# RT- 1 hour after twenty

fifth fraction of radiotherapy; CA4P4 – 4 hours after the fourth dose of CA4P; 72h 4- 72 hours

after the fourth dose of CA4P; 6# RT- 1 hour after sixth fraction of radiotherapy; CA4P3 – 4

hours after the third dose of CA4P.

Table 7.7 DCE-CT derived median Blood Flow (BF) values (ml/100ml/min) and percentage

change from previous time point for patients with SCC Head & Neck receiving

weekly CA4P, cetuximab and RT (UKR104 cohort 6).

249

PreCA4P 4h 6-8h 1 week0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Whi

te c

ell c

ount

Time points

JC36 HC38 GK39 JG40 Mean

Figure 7.5

Graph of individual and group mean changes in white cell count for HNSCC patients

receiving weekly CA4P, weekly cetuximab and RT (Cohort 6), plotted at the

following time points: PreCA4P- after third or fourth fraction of radiotherapy in week

of sampling, after second dose of cetuximab and prior to CA4P; 4h- 4 hours after

CA4P; 6- 8h- 6 to 8 hours after CA4P; 1 week- 7 days after CA4P.

250

PreCA4P 4h 6-8h 1 week0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Neu

troph

il co

unt

Time points


Figure 7.6

Graph of individual and group mean changes in neutrophil count for HNSCC





251

PreCA4P 4h 6-8h 1 week0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

Lym

phoc

yte

coun

t

Time points


Figure 7.7

Graph of individual and group mean changes in lymphocyte count for HNSCC





252

PreCA4P 4h 6-8h 1 week-0.05

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

Mon

ocyt

e co

unt

Time points


Figure 7.8

Graph of individual and group mean changes in monocyte count for HNSCC





253

JC36 PreCA4P 4h 6-8h 1 week

Hb 135 137 140 124

Plt 502 490 473 387

WBC 7.2 13.8 9.9 6.8

Neu 5.8 12.9 8.5 5.3

Lym 0.7 0.4 0.7 1.1

Mon 0.3 0.4 0.6 0.4

HC38 PreCA4P 4h 6-8h 1 week

Hb 131 125 138 129

Plt 168 138 145 145

WBC 3.5 2.3 8 3.1

Neu 2.1 1.6 7.1 2

Lym 0.9 0.6 0.6 0.6

Mon 0.4 0 0.2 0.3

GK39 PreCA4P 4h 6-8h 1 week

Hb 134 136 131 138

Plt 254 237 248 323

WBC 8 7.2 9.9 4.4

Neu 6.6 6.5 8.9 3.2

Lym 0.7 0.6 0.4 0.6

Mon 0.7 0.1 0.5 0.5

JG40 PreCA4P 4h 6-8h 1 week

Hb 119 127 132 117

Plt 333 334 346 297

WBC 6.2 11.7 10.9 6.4

Neu 3.8 10 9 4.6

Lym 1.8 1.4 1.4 1.3

Mon 0.4 0.1 0.3 0.4

Table 7.8 Full blood count results for head and neck cancer patients receiving CA4P, cetuximab and radical radiotherapy (UKR104 cohort 6).

254

Pre CA4P 4h 6-8h 1 week-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

VEG

F (p

g/m

l)

Time points


Figure 7.9

Graph of individual and group mean changes in plasma VEGF concentration for

HNSCC patients receiving weekly CA4P, weekly cetuximab and RT (Cohort 6),

plotted at the following time points: PreCA4P- after third or fourth fraction of

radiotherapy in week of sampling, after second dose of cetuximab and prior to

CA4P; 4h- 4 hours after CA4P; 6- 8h- 6 to 8 hours after CA4P; 1 week- 7 days after

CA4P.

255

Pre CA4P 4h 6-8h 1 week

0

20

40

60

80

100

120

140

160

180

200

220

VEG

FR1

(pg/

ml)

Time points


Figure 7.10

Graph of individual and group mean changes in plasma VEGFR1 concentration for





CA4P.

256


0

20

40

60

80

100

120

140

160

180

200

220

G-C

SF (p

g/m

l)

Time points


Figure 7.11

Graph of individual and group mean changes in plasma G-CSF concentration for





CA4P.

257

Pre CA4P 4h 6-8h 1 week0

1000

2000

3000

4000

SDF-

1 (p

g/m

l)

Time points


Figure 7.12

Graph of individual and group mean changes in plasma SDF-1 concentration for


plotted at the following time points: PreCA4P- after 3 to 4 fractions of radiotherapy,

after second dose of cetuximab and prior to CA4P; 4h- 4 hours after CA4P; 6- 8h- 6

to 8 hours after CA4P; 1 week- 7 days after CA4P.

258

A VEGF (pg/ml)


JC36 54 107 70 79

HC38 0 0 0 13

GK39 42 69 45 0

JG40 0 96 58 145

B VEGF R1 (pg/ml)


JC36 131 201 147 60

HC38 103 176 218 72

GK39 50 85 128 38

JG40 0 92 178 30

C G-CSF (pg/ml)


JC36 81 77 53 80

HC38 20 39 91 29

GK39 83 147 194 50

JG40 21 54 56 27

D SDF-1 (pg/ml)


JC36 2924 3048 2753 2520

HC38 3092 2796 2859 3063

GK39 1845 1994 1953 2067

JG40 2390 2580 2944 2341

Table 7.9

ELISA results for head and neck cancer patients receiving CA4P, cetuximab and

radical radiotherapy (UKR104 cohort 6).

259

CHAPTER 8

!

Concluding discussion

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