WB-DWI vs FDG PET/CT in

Lymphoma

An Exploratory Study of Pre-treatment Staging and

Post-treatment Assessment in Malignant Lymphoma
by Whole Body Diffusion-weighted MR Imaging (WB-
DWI) and ADC-mapping in comparison to18F-FDG
PET/CT

RMH CCR No: 3275

Study Sponsor: The Royal Marsden NHS Foundation Trust

Chief Investigators: Dr. Sue Chua & Dr. Dow-Mu Koh

Title: An Exploratory Study of Pre-treatment Staging and Post-treatment Assessment in
Malignant Lymphoma by Whole Body Diffusion-weighted MR Imaging (WB-DWI) and
ADC-mapping in comparison to18F-FDG PET/CT.

Short Title: WB-DWI vs FDG PET/CT in Lymphoma

Protocol version: Version 4

Version data: 04/12/2009

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Investigators and contact details:

PET/CT and Radiology Investigator: Dr. Sue Chua

MRI Functional Imaging Investigator:
PET/CT Investigator:
PET/CT and Radiology investigator
Department of Nuclear Medicine, PET and Radiology
Royal Marsden Hospital
Downs Road
Sutton, Surrey SM2 5PT
United Kingdom
Phone: 0208 6613544
Fax: 0208 6613290
e-mail: sue.chua@rmh.nhs.uk
Dr. Dow-Mu Koh
Consultant Radiologist (Functional Imaging),
Department of Radiology
Royal Marsden Hospital
Downs Road
Sutton, Surrey SM2 5PT
Tel: 0208 6613857
Fax: 0208 6613901
Email: Dow-Mu.Koh@icr.ac.uk
Dr. Gary Cook
Consultant in Nuclear Medicine and PET
The Royal Marsden Hospital
Downs Road, Sutton, Surrey SM2 5PT
Tel: 208 6613921
Fax: 208 6613290
Email: gary.cook@icr.ac.uk
Dr. Bhuey Sharma
Department of Radiology
Royal Marsden Hospital
Downs Road
Sutton, Surrey SM2 5PT
Tel: 0208 6613652
Fax: 0208 6613901
Email: bhuey.shama@rmh.nhs.uk

Radiology investigator Dr. Gina Brown

Department of Radiology
Royal Marsden Hospital
Downs Road
Sutton, Surrey SM2 5PT
United Kingdom
Tel: 0208 6613964
Fax: 0208 6613901
Email: gina.brown@rmh.nhs.uk

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MRI Physicist Mr. David Collins
Department of Radiology
Clinical Magnetic Resonance
Royal Marsden Hospital
Downs Road
Sutton, Surrey SM2 5PT
Phone:020 86613709
e-mail: david.collins@rmh.nhs.uk
Clinical Investigator Prof. David Cunningham
Department of Medicine
Royal Marsden Hospital
Downs Road
Sutton, Surrey SM2 5PT
United Kingdom
Phone: 020 86613156
Fax: 020 86439414
e-mail: david.cunningham@rmh.nhs.uk
Clinical Investigator Dr. Ian Chau
Department of Medicine
Royal Marsden Hospital
Downs Road
Sutton, Surrey
SM2 5PT
Tel: 020 86613582
Fax: 020 86613890
Email: ian.chau@rmh.nhs.uk
Statistician Ms. Karen Thomas
Clinical Research and Development 
Royal Marsden Hospital
Downs Road
Sutton, Surrey
SM2 5PT
Tel: 0208 6613441
Email: karen.thomas@rmh.nhs.uk
Trial Coordinator and Data Centre Ms. Yvonne Fox
Contacts Department of Nuclear Medicine
Royal Marsden Hospital
Downs Road
Sutton, Surrey SM2 5PT
United Kingdom
Phone: 0208 6613760
Fax: 0208 6616761
e-mail: yvonne.fox@rmh.nhs.uk

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Trial Management Group

Dr Sue Chua, Dr Dow-Mu Koh, Dr Gary Cook, Mr David Collins, Professor David
Cunningham, Dr Ian Chau, Ms Karen Thomas, Ms Yvonne Fox.

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Table of Contents

1 Protocol synopsis …………………………………………………………... 8

2 Background and Rationale …………………………………………………. 10
2.1 Background and Rationale for Diffusion Weighted- MR (DW-MRI)
Imaging in nodal disease …………………………………………... 10
3 Study Hypothesis ……………………………………………………………. 11
4 Study Objectives ……………………………………………………………. 11
5 Study Design ……………………………………………………………. 12
5.1 Study flow chart …………………………………………………… 12
5.2 Study Methods …………………………………………………… 12
5.2.1 Study population & Method ………………………… 12
5.2.2 Biomarker Analysis …………………………………. 13
6 Inclusion and exclusion criteria ……………………………………………….. 14
6.1 Inclusion criteria ……………………………………………………. 14
6.2 Exclusion criteria ……………………………………………………. 15
6.3 Subject withdrawal criteria ………………………………… 15
7 Study Organisation …………………………………………………… 15
7.1 Responsibility …………………………………………………… 15
7.2 Risk Assessment ……………………………………………… 15
7.3 Trial management strategy …………………………………. 15
7.4 Study monitoring …………………………………………… 16
7.5 Data monitoring ………………………………………….. 16
8 Study Procedures ……………………………………………………………. 16
8.1 Recruitment …………………………………………………... 16
8.2 Consent ………………………………………………………. 16
8.3 Patient registration …………………………………………… 16
8.4 Subject withdrawal ……………………………………………... 17
8.5 Outcome reporting …………………………………………… 17
8.6 Premature discontinuation of the study …………………………. 17
9 Study Assessments …………………………………………………….. 17
10 Statistical considerations ……………………………………………………. 17
11 Ethical considerations ……………………………………………………. 18
11.1 General ethical issues …………………………………………… 18
11.2 Informed consent …………………………………………… 18
12 Data Handling and Record Keeping ………………………………….. 18
13 Quality Control and Quality Assurance ……………………………….…. 19
14 Financing, Indemnity and Insurance …………………………………. 19
15 Publication Policy …………………………………………………………... 19
16 References ……………………………………………………………… 19
17 Appendices ………………………………………………………………. 23
1 Summary of trial procedures …………………………………… 23
2 CRF for WB DW MR Study …………………………………… 24
3 CRF for WB 18F-FDG PET/CT Study …………………………. 25
4 Re-assessment CT scan final report …………………………. 26
5 Instructions for WB DW MRI and 18F-FDG-PET/CT analysis ……… 27

6
6 Instructions for contrast enhanced CT analysis ........................... 30
7 Patient information sheet …………………………………….. 31
8 Consent form ........................................................................... 32
9 Letter to GP .......................................................................... 34

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1. Protocol synopsis

Title An Exploratory Pre-treatment Staging and Post-treatment

Assessment in Malignant Lymphoma by Whole Body Diffusion-
weighted MR Imaging (WB-DWI) and ADC-mapping in comparison
to18F-FDG PET/CT

Short title DWI vs FDG PET/CT in Lymphoma

Start and End We anticipate the project will run for 12 months (start date
Dates of Study 15.01.2010) with an accrual rate of one patient per week. Data
analysis will run concurrently with the data acquisition. The study will
be completed by January 2011.

Study design A single centre non-randomised exploratory study

Number of 25 patients in total

patients
Primary To prospectively assess the capability of WB-DWI with ADC
objectives mapping, relative to integrated fluorine-18 fluorodeoxyglucose (18 F-
FDG) positron emission tomography (PET)/computed tomography
(CT), in the pre-treatment staging and post-treatment assessment of
malignant lymphoma.

Secondary (1) To determine whether WB-DWI is sensitive for the pre-treatment

objectives staging and post-treatment assessment of lymphoma by comparing
with reference test (18F-FDG PET/CT)positive subjects who also test
positive with WB-MRI. Both nodal and extranodal lymphomas are
highly cellular so should be readily amenable to detection by WB-
DWI.

(2) To compare the ADC values of lymphoma masses before and

after treatment to determine if patients with lymphoma showing
measurably lower pre-treatment ADC have a better response to
standard 1st line treatment; and whether effective therapy results in
an ADC rise. If this is the case responders and non-responders
might be identifiable for future treatment stratification.

Primary endpoint The primary outcomes of this study are: 1) to estimate the
percentage agreement in baseline stage for WB-DWI compared to
PET/CT; 2) to estimate the sensitivity and specificity of post-
treatment WB-DWI in detecting response (CR or PR) when
compared to the reference of post-treatment PET/CT.

Inclusion criteria - Age 18 and above

- Patients with nodal or/and extranodal lesions at least 2cm in
size
- All HD and NHL patients who are undergoing both baseline
and post-treatment18F-FDG PET scans scheduled as part of

8
 routine clinical management will be eligible for the study.
- Informed written consent
- Willingness and ability to comply with scheduled study visits
and tests
Exclusion criteria - Pregnant or lactating
- Concomitant uncontrolled medical conditions
- Poorly controlled diabetes mellitus
- Non-FDG-avid and structurally non-measurable lesions on
pre-treatment 18F-FDG-PET/CT and contrast enhanced CT
respectively
- Contraindications to MR imaging

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2. Background and Rationale

Functional imaging with 18F-FDG PET/CT is a valuable tool in the management of

lymphoma, improving staging accuracy and allowing early and more sensitive
assessment of treatment response than conventional methods1-8. 18F-FDG PET/CT does
however show a significant false negative rate in lymphomas with low proliferative
fractions, which show poor FDG uptake; and inflammatory/infective foci may give rise to
false positivity. It also has the limitations of being relatively costly and time-consuming,
and involves patient radiation exposure and associated logistical/radiation protection
issues.

WB-DWI, like PET/CT, is a functional imaging technique, deriving its image contrast from
differences in the diffusion of water molecules within tissues. The degree of water
diffusivity can be quantified by the Apparent Diffusion Coefficient (ADC) calculated using
a range of diffusion weightings. Diffusion correlates inversely with tissue cellularity and
density of cell membranes so that ADC values are low in most tumours relative to normal
tissues. WB-DWI has been used for the detection and characterisation of malignant
diseases (e.g lung9,10 and breast cancers11-13), but has not been applied for tumour
segmentation or the assessment of treatment response. Studies using regional diffusion-
weighted scans have shown that effective tumour therapy results in an increase in
tumour ADC values. Pre-treatment ADC values may also be of prognostic importance
since studies in colorectal carcinoma14,15 and gliomas16,17 have shown that tumours with
lower baseline pre-treatment ADC values responded better to chemo/radiotherapy.

WB-DWI has not previously been applied to the evaluation of lymphoma, but the high
cellularity and cell membrane density of lymphoid tissue has been shown to render it
readily visualizable by the technique and we anticipate that this will make lymphoma
particularly amenable to detection and monitoring by WB-DWI. Accurate and timely
assessment of response to therapy is especially important in lymphoma since a
significant proportion of patients do not respond to first-line therapy and require a prompt
change in treatment regimen. Functional imaging with PET/CT has already enabled
objective assessment of metabolic response well before morphological changes become
evident, and we hypothesize that WB-DWI may also prove valuable in this role.

The purpose of this study is to investigate the potential clinical role of WB-DWI in the
detection, staging and assessment of response to therapy in Hodgkin's and non-
Hodgkin's lymphoma, and compare its value to that of 18F-FDG PET/CT in this scenario.

Please note that for the purposes of this exploratory study only cases of high grade NHL
and Hodgkin’s lymphoma. for which 18F-FDG PET/CT is the accepted reference imaging
method, have been included in order to avoid bias due to 18F-FDG PET/CT’s low
sensitivity in low grade NHL. The latter group of patients do not currently undergo routine
clinical PET/CT scanning.

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2.1 Background and Rationale for Diffusion Weighted- MR (DWI) Imaging In nodal
disease

As described above, diffusion-weighted DWI can quantify water diffusion, which is

restricted in highly cellular tissues. The measured apparent diffusion coefficient (ADC)
therefore provides a non-invasive index of cellularity. We will evaluate the potential of
these approaches in the initial staging and post-treatment assessment of lymphoma.
The outcome of the WB DWI scans will be compared to 18F-FDG PET/CT, other imaging
modalities, clinical indices (over 6 months) and histology.

To date, a few small series have shown the potential value of DWI in detecting tumour
foci within lymph nodes through measuring restriction of ADC within nodes18-24.

Stecco A et al. conducted a pilot study comparing the accuracy of 18F-FDG PET/CT and
whole-body DW-I in staging several malignancies. 15 out of 29 patients had malignant
lymphoma. The authors concluded that the whole-body DWI protocol provided a fast
whole-body examination with high specificity and NPV of 98% and 99% respectively18.
Holzapfel K et al.19 studied 55 enlarged cervical nodes with a small number (n=6) being
due to NHL. They demonstrated that ADC values of malignant lymph nodes were
significantly lower than ADC values of benign lymph nodes. 94.3% of lesions were
correctly classified as benign or malignant using a threshold ADC value of 1.02x10(-
3)mm(2)/s. This showed that DWI using a SSEPI sequence allows reliable differentiation
between benign and malignant cervical lymph nodes19. King AD et al.20 prospectively
determined the diagnostic accuracy of DWI imaging for discrimination of malignant neck
nodes due to lymphoma, squamous cell carcinoma (SCC), and undifferentiated
nasopharyngeal carcinoma (NPC). The measured mean ADC values for lymphoma (n =
8), NPC (n = 17), and SCC (n = 18) were (0.664 +/- 0.071 [standard deviation]) x 10(-3)
mm(2)/sec, (0.802 +/- 0.128) x 10(-3) mm(2)/sec, and (1.057 +/- 0.169) x 10(-3)
mm(2)/sec, respectively, with significant differences between SCC and lymphoma or
NPC (P < .001) and between NPC and lymphoma (P = 0.04). The study showed the
potential of DWI in differentiating between malignant nodes of SCC, lymphoma, and
NPC using ADC threshold values20. However, DWI and the derived quantitative ADC
values have not been used specifically for the staging and post-treatment evaluation of
residual masses following first line chemotherapy. Organising granulation tissue/fibrosis
is relatively paucicellular, being composed of scattered fibroblasts and inflammatory cells
within areas of collagen deposition, whereas lymphomas are highly cellular tumours. We
hypothesise that on the basis of the available evidence summarised above, DWI should
therefore be an effective modality for discriminating between these causes of a residual
post-treatment mass.

3. Hypothesis

Whole-body DW MR imaging can be used for pre-treatment and post-treatment

assessment in lymphoma patients with accuracy comparable to that of FDG PET/CT
(greater than 70% accuracy). At this small sample size this is necessarily an

11
exploratory study and further studies based on larger sample sizes will be required to
test the hypothesis more robustly.

4. Study Objectives

 Primary Objective:

To prospectively assess the capability of WB-DWI with ADC mapping, relative to

integrated fluorine-18 fluorodeoxyglucose (18 F-FDG) positron emission tomography
(PET)/computed tomography (CT), in the pre-treatment staging and post-treatment
assessment of malignant lymphoma.

 Secondary Objectives:

(1) To determine whether WB-DWI is a sensitive imaging biomarker for pre-treatment

staging and post-treatment assessment of lymphoma. Both nodal and extranodal
lymphomas are highly cellular so should be readily amenable to detection by WB-DWI.

(2) To compare the ADC values of lymphoma masses before and after treatment to
determine if patients with lymphoma showing measurably lower pre-treatment ADC have
a better response to standard 1st line treatment; and whether effective therapy results in
an ADC rise. If this is the case responders and non-responders might be identifiable for
future treatment stratification.

5. Study Design

A prospective study of patients with newly diagnosed non-Hodgkin's and Hodgkin's

lymphoma prior to and following 1st line chemotherapy. We plan to evaluate the
diagnostic accuracy of WB-DWI in the pre-treatment staging and post-treatment
assessment of lymphoma and compare this with the results of the routine combined
functional and anatomical 18F-FDG PET/CT scans also performed at baseline and at
completion of 1st line treatment.

5.1 Study plan flow chart:

Pre-treatment Imaging → 1st line Chemotherapy → Post-treatment Imaging* ----→ Follow-up at 6 months

Routine :**CeCT NCAP Routine :*CeCT NCAP Imaging : Routine CeCT

: 18F-FDG PET/CT : 18F-FDG PET/CT : 18F-FDG PET/CT
(if available)

Research: WB-DWI Research: WB-DWI Histology: if available

* Post-treatment imaging (WB DW MRI & FDG PET/CT will be done at 4 weeks following the completion of
the 1st line treatment.
**CeCT NCAP: Contrast-enhanced CT of neck, chest, abdomen & pelvis

5.2 Study Methods

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5.2.1 Study Population and Method

This is a single-stage exploratory study. Patients will be scanned using 18F-FDG PET/CT
(from vertex to thigh) and WB-DW MRI (from vertex to thigh) one at baseline and 4
weeks after completion of first-line treatment. At baseline independent reviewers blinded
to patient numbers will assess each scan and record the disease stage. At the end of
treatment independent reviewers will asses each pair of scans (baseline and end
treatment) and record the disease response as CR, PR, SD or PD.

25 patients with newly diagnosed histologically proven lymphoma (NHL &HD) with at
least one site of disease measuring > 2 cm in diameter, scheduled to be treated using
standard 1st line chemotherapy, and who consent to take part in the study will be
prospectively evaluated using WB-DWI imaging (from skull base to upper thighs) at
baseline and at completion of treatment (1.5 Tesla WB- DWI:, Echo-planar spin-echo
technique, free breathing, STIR fat suppression, three b-values 0, 300 and 900 s/mm2).
Patients with contraindications to MR or PET imaging will be excluded. As there is no
defined gold standard for lesion detection in lymphoma, WB-DWI findings will be
corroborated with the most sensitive currently available detection method, 18F-FDG
PET/CT. The clinical outcome data will be based on imaging at 6 months by routine
CeCT NCAP, as well as 18F-FDG PET/CT and/or histology if available.

5.2.2 Biomarker Analysis

Study measurements

Differences in mean ADC values between baseline(pre-treatment) and post-treatment

will be documented. ADC values will be calculated on a per patient and a per lesion
basis, to include the largest 5 lesions per patient. The median ADC value will be
recorded for each of the five lesions, and the mean of the medians will be recorded for
each patient. For each patient and lesion the difference in mean/median ADC between
baseline and post-treatment will be calculated. Patients that are alive and free from
progression at 6 months (primary endpoint) and show imaging evidence of response (CR
or PR) will be considered ‘responders’ and those that either die or progress before then
will be considered ‘non responders’.

(1) WB-DWI and 18F-FDG PET/CT will be independently reviewed and scored by two
radiologists (including one radiologist with additional specialization in nuclear medicine)
for the presence, location, and confidence for suspected lesions. Visual and
semiquantitative assessment using SUV mean and SUVmax will be employed in scoring
the 18F-FDG PET/CT scans (see Appendix 5).

(2) In each patient, the median ADC total for each of the largest 5 lesions present,
(calculated using all 3 b-values) and the median high (calculated using b=300 and 900
s/mm 2) for nodal and extranodal lesions will be calculated.

(3) The b=900 s/mm 2 image and ADC values of lymphomatous disease will be used as
a basis for volume segmentation of lymphomatous disease. We will investigate and
define the level of acceptability for lymphomatous disease detection using WB-DWI.

13
Primary outcome

The primary outcomes of this study are: (1) to estimate the percentage agreement in
baseline stage for WB-DWI compared to PET/CT and show that this is better than
70%; (2) to estimate the sensitivity and specificity of post-treatment WB-DWI in detecting
response (CR or PR) when compared to the reference of post-treatment PET/CT.

Secondary outcomes

Secondary outcomes are as follows:

1) To estimate the difference in baseline ADC, and ADC change (baseline to post-
treatment) in responders vs non-responders.

2) To assess the ability of ADC change (baseline to post-treatment) to predict response

at 6 months, where response at 6 months is assessed using PET/CT and histology
(where available).

3) To calculate the per-lesion sensitivity of baseline WB-DWI, using PET/CT as the

reference.

Analysis methods – primary outcomes

Staging agreement will be calculated as the number of patients with the same baseline
stage using PET/CT and WB DW-MRI, divided by the total number of patients. A one-
sided exact biomial test with alpha=0.05 will be used to test the null hypothesis
that agreement is no more than 70%. In addition a Kappa statistic to measure
agreement between these two methods will be calculated.

Sensitivity will be the number of patients declared as CR/CRu/PR using both end of
treatment scans (WB-DWI and PET/CT), divided by the number of patients with
CR/CRu/PR on PET/CT.

Specificity will be the number of patients declared as SD/PD using both end of treatment
scans (WB-DWI and PET/CT), divided by the number of patients with SD/PD on
PET/CT.

Analysis methods – secondary outcomes

Mean per-patient baseline ADC, and change in per-patient mean ADC will be
summarised with descriptive statistics, separately in responders and non-responders. In
an exploratory analysis, a two-tailed t-test (or Mann-Whitney if considered more
appropriate) will be used to compare ADC values in the two groups. This analysis will be
performed twice: once for mean overall ADC (all b-values) and once for mean high ADC
(b-values >100).

A ROC curve will be constructed to assess the sensitivity and specificity of change in
mean (per-patient) ADC in predicting status at 6 months. This analysis will be performed
twice: once for mean overall ADC (all b-values) and once for mean high ADC (b-values
>100).

14
Per-lesion sensitivity will be measured by recording each lesion detected using PET/CT,
and noting whether or not it was also detected using WB-DWI. The sensitivity will be
calculated as the total number of lesions detected on both scans, divided by the total
number of lesions detected on PET/CT. (In each patient a maximum of 5 lesions will be
recorded)

6. Inclusion and Exclusion Criteria

6.1 Inclusion criteria

i) Age 18 and above

ii) Patients with nodal or/and extranodal lesions at least 2cm in size
iii) All ND and NHL patients who are undergoing both baseline and post-
treatment18F-FDG PET scans scheduled as part of routine clinical
management will be eligible for the study.
iv) Informed written consent
v) Willingness and ability to comply with scheduled study visits and tests

6.2 Exclusion criteria

i) Pregnant or lactating
ii) Concomitant uncontrolled medical conditions
iii) Poorly controlled diabetes mellitus
iv) Non-FDG-avid and structurally non-measurable lesions on pre-treatment
18
F-FDG-PET/CT and contrast enhanced CT respectively
v) Contraindications to MR imaging

6.3 Subject withdrawal criteria

1) Intolerable adverse effects as judged by the investigator or the patient

2) Patient decision to discontinue treatment
3) Pregnancy
4) The development of any intercurrent medical condition which in the opinion of the
investigator may affect patient safety, the ability to deliver treatment or the ability to
assess response to treatment.

A patient who is withdrawn from the trial will be excluded from the study. If a recruited
patient is lost to follow-up or is ineligible for analysis at the primary endpoint, the patient
will be replaced if possible.

7. Study Organisation

7.1 Responsibility

The Chief Investigator will take primary responsibility for the conduct of the trial under
the EU Clinical Trials Directive (2001/20/EC). The trial conduct will conform to ICH GCP
guidelines and falls within the Research Governance Framework Guidelines.

7.2 Risk Assessment

15
Risk assessment of this trial has been performed with a risk assessment tool (IoP/SMAM
Clinical Trials Co-ordinating Committee Risk Assessment Tool) used by the Royal
Marsden Hospital NHS Trust’s Research and Development department.

7.3 Trial Management Strategy

The overall monitoring of safety issues related to the trial will be performed by the trial
management group. The trial management group includes the chief investigator, the
study coordinator and the statistician. Members of the RMH Radiology, Nuclear Medicine
and Lymphoma Clinical Trials Units also meet at the team’s regular research meetings to
consider safety issues. Regular contact will be maintained with the CCR at the Royal
Marsden. A data monitoring committee will be convened to oversee issues relating to
both toxicity and efficacy of treatment.

7.4 Study Monitoring

Monitoring of the study will be according to ICH-GCP standards and within the
framework of the Royal Marsden Hospital’s Research and Development/Ethics
monitoring policies. All patients will be registered with the Radiology Department Trials
Office on the day of consent or shortly afterwards.

7.5 Data monitoring

Eligibility criteria will be reviewed by the data manager on potential recruitment of

patients into the trial. Consent forms will be reviewed for accuracy, dates, signatures
and completeness. The data stamp or version number of the patient information sheet
and study protocol currently in use will form part of the normal eligibility criteria to ensure
up to data study documentation are being used in the recruitment process. CRFs will be
checked by the data managers for completeness, as data is entered into the database.
Statistical data monitoring of the database will be performed at regular intervals to
ensure completeness and accuracy of data.

8. Study Procedures

8.1 Recruitment

Suitable patients who have been histologically diagnosed with Hogkkin’s disease (HD)
and Non-Hodgin’s Lymphoma (NHL) who have had a pre-treatment FDG PET/CT will be
approached for consideration of entry into DWI vs FDG PET/CT Lymphoma trial whilst
attending outpatient clinics. They will be given verbal and written information about the
trial and informed that their entry into the study is entirely voluntary. They will then be
given adequate time to consider whether they wish to enter the study or not (a minimum
of 24 hours). Patient recruitment and screening will only commence once the appropriate
official notification has been received by the chief investigator that the trial is open for
recruitment. Study-specific procedures will only commence once the patient has signed
informed consent.

8.2 Consent

16
Consenting procedures will conform to GCP and local and national regulations. A copy
of the patient information sheet and consent form is given in the appendices to this
protocol. Written informed consent will be obtained for entry into the imaging trial.

8.3 Patient registration

Patients should be registered with the Radiology/Nuclear Medicine Department on the

day of consent for this study or as soon as possible thereafter.

Please contact the Trials Office on + 44 (0)20 8661 3544. Patient eligibility will be
checked at the time of registration and will include the inclusion and exclusion criteria
listed above.

8.4 Subject and drug withdrawal

A patient will be immediately withdrawn from the study if any of the criteria in Section 6.3
are met. Any CRFs will be completed.

8.5 Outcome reporting

All of the patients registered will be accounted for. The outcomes of patients who were
not evaluable or who died or withdrew before treatment began will be specified. The
number of patients lost to follow up will be given and the distribution of follow up time
also given.

8.6 Premature discontinuation of study

The trial management group in conjunction with the chief investigator will review new
published evidence regularly. Premature discontinuation may occur because of a
regulatory authority decision, a change in opinion of the independent ethics committee/
institutional review board, drug safety problems or at the discretion of the Chief
Investigator in conjunction with the CCR. If the trial is prematurely terminated, all study
staff and investigators will be notified by the Principal Investigator. All trial materials and
CRFs must be completed to the greatest extent. Patients already enrolled will continue
to be followed up as per protocol.

9. Study Assessments

Safety reporting for serious adverse events

As this is an exploratory study, no adverse effects are expected from the DW MRI scans.
However any serious adverse events will be reported to the Chief/Principal Investigator
and co-investigators and managed appropriately. The Chief/Principal Investigator has
responsibility to notify the ethics committee.

17
10. Statistical considerations

Based on an expected level of agreement of 95%, the study will have at least 80%
power to show that the level of agreement is >70%, using a one-sided alpha of
0.05 and an exact binomial test (calculated using nQuery version 6.0)

Agreement in at least 23/25 patients will be required in order to declare that

staging using DW-MRI is acceptable when compared to PET-CT.

11. Ethical considerations

11.1 General ethical issues

This responsible investigator will ensure the study is be carried out in accordance with
the World Medical Association Declaration of Helsinki (1964) and the Tokyo (1975),
Venice (1983), Hong Kong (1989), South Africa (1996) and Scotland (2000)
amendments, or the laws and regulations of the country, whichever provides the
greatest protection for the patient.

The study protocol will be given approval by the REC (Research Ethics Committee) and
will only be open to recruitment following the approval being granted. Subjects will only
be allowed to enter the study provided they have given written informed consent
following a full explanation of the study and reading of the information sheet (Appendix
10 and 11). The patient information sheet may be translated into other languages if
necessary.

Subjects will be informed that they have the right to withdraw from the study at any stage
without prejudice to their further treatment and care and without having to give a reason.
This study may be terminated at the request of the Principal Investigator or the
Independent Ethics Committee if during the course of the study concerns about the
safety or efficacy about the proposed treatment emerge. The Principal Investigator will
update the ethics committee of any new information relating to the trial treatment where
appropriate.

11.2 Informed consent

Written informed consent will be obtained from each patient in accordance with
regulatory requirements, GCP and the Declaration of Helsinki. The subject will have the
exact nature of the study explained to them (written and verbal), and the anticipated
benefits and known side-effects. They will be advised that they are free to withdraw from
the study without obligation. The consent form will also request permission for personnel
involved in the research to have access to the subject’s medical records.
Both the person taking consent and the patient should personally sign and date the form.
The original copy of the signed Consent Form must be retained by the Investigator in the
Study File, a copy will be put in the subject’s notes, and a copy of the signed Consent
Form will be given to the subject. Patients will be asked permission to inform their GP of
participation within this trial and if they agree, a letter will be sent to their GP (Appendix
12).

12. Data handling and Record Keeping

18
Data will be collected and maintained according to ICH-GCP standards. The data
manager assigned to the study will enter data from the CRFs into a trial-specific
database which will be run off the main HIS database. All source documents relating to
individual research participants will be anonymised and maintained securely within the
hospital (locked room). The computer database is password protected and will hold the
decode for the identification of the patient. Personnel who have access to the database
are legally bound by the confidentiality agreement in their contract of employment.

Source documents will be maintained for 15 years and will be available for inspection by
authorised staff including the Chief/Principal Investigator, Study Coordinator, Clinical
Trials Manager, Research Nurse and statistician. Source documents will be made
available if requested for monitoring and audit purposes to the Ethics and Research and
Development departments and for inspection by regulatory bodies.

13. Quality Control and Quality Assurance

The monitoring processes above will form the mainstay of quality control within the
study. Laboratory tests are subject to internal validation and standardisation processes.
Imaging will be independently reviewed by one radiologist for the outcome of response
to therapy. Established secure and confidential computerised systems for recording data
are in place. Investigators and study personnel will be made available for possible
audits and inspections by the institutional review board or Ethic Committee and by the
regulatory bodies. All source documentation and the site study file will be available for
inspection.

14. Financing, Indemnity and Insurance

The cost of the WB DW MRI scans will be supported by the Royal College of
Radiologists Research Funding Scheme (Small Project Grant) and The Royal
Marsden Radiology Department Research Fund. The usual NHS indemnity processes
are in place to cover negligent harm causes through participation in this trial. No cost
required for FDG PET imaging as this is part of patients’ routine clinical management.

15. Publication Policy

The aim of the investigators is to author and publish the mature results of this study in a
peer reviewed journal. All presentations and publications require authorisation from the
Principle Investigator.

19
16. References

1. Terasawa T, Lau J, Bardet S, et al. Fluorine-18-fluorodeoxyglucose positron emission

tomography for interim response assessment of advanced-stage Hodgkin's lymphoma
and diffuse large B-cell lymphoma: a systematic review. J Clin Oncol. 2009 Apr
10;27(11):1906-14. Epub 2009 Mar 9.

2. Terasawa T, Nihashi T, Hotta T, Nagai H. 18F-FDG PET for posttherapy assessment

of Hodgkin's disease and aggressive Non-Hodgkin's lymphoma: a systematic review. J
Nucl Med. 2008 Jan;49(1):13-21. Epub 2007 Dec 12.

3. Brepoels L, Stroobants S. PET scanning and prognosis in Hodgkin's lymphoma. Curr

Opin Oncol. 2008 Sep;20(5):509-16.

4. Jerusalem G, Hustinx R, Beguin Y, Fillet G. Evaluation of therapy for lymphoma.

Semin Nucl Med. 2005 Jul;35(3):186-96.

5. Schiepers C, Filmont JE, Czernin J. PET for staging of Hodgkin's disease and non-
Hodgkin's lymphoma. Eur J Nucl Med Mol Imaging. 2003 Jun;30 Suppl 1:S82-8.

6. Pelosi E, Pregno P, Penna D. Role of whole-body [18F] fluorodeoxyglucose positron

emission tomography/computed tomography (FDG-PET/CT) and conventional
techniques in the staging of patients with Hodgkin and aggressive non Hodgkin
lymphoma. Radiol Med. 2008 Jun;113(4):578-90.

7. Allen-Auerbach M, de Vos S, Czernin J. The impact of fluorodeoxyglucose-positron

emission tomography in primary staging and patient management in lymphoma patients.
Radiol Clin North Am. 2008 Mar;46(2):199-211, vii.

8. Juweid ME. 18F-FDG PET as a routine test for posttherapy assessment of Hodgkin's
disease and aggressive non-Hodgkin's lymphoma: where is the evidence? J Nucl Med.
2008 Jan;49(1):9-12. Epub 2007 Dec 12.

9. Ohno Y, Koyama H, Onishi Y, et. Al. Non-small cell lung cancer: whole-body MR
examination for M-stage assessment--utility for whole-body diffusion-weighted imaging
compared with integrated FDG PET/CT. Radiology. 2008 Aug;248(2):643-54.

10. Yi CA, Shin KM, Lee KS,et.al. Non-small cell lung cancer staging: efficacy
comparison of integrated PET/CT versus 3.0-T whole-body MR imaging. Radiology.
2008 Aug;248(2):632-42.

11. Lo GG, Ai V, Chan JK,et. al. Diffusion-weighted magnetic resonance imaging of

breast lesions: first experiences at 3 T. J Comput Assist Tomogr. 2009 Jan-
Feb;33(1):63-9.

20
12. Yili Z, Xiaoyan H, Hongwen D, et. al. The value of diffusion-weighted imaging in
assessing the ADC changes of tissues adjacent to breast carcinoma. BMC Cancer.
2009 Jan 14;9:18.

13. Yoshikawa MI, Ohsumi S, Sugata S, et. al. Relation between cancer cellularity and
apparent diffusion coefficient values using diffusion-weighted magnetic resonance
imaging in breast cancer. Radiat Med. 2008 May;26(4):222-6.

14. Marugami N, Tanaka T, Kitano S, et. al.Early Detection of Therapeutic Response to

Hepatic Arterial Infusion Chemotherapy of Liver Metastases from Colorectal Cancer
Using Diffusion-Weighted MR Imaging. Cardiovasc Intervent Radiol. 2009 Feb 24.

15. Cui Y, Zhang XP, Sun YS, et al. Apparent diffusion coefficient: potential imaging
biomarker for prediction and early detection of response to chemotherapy in hepatic
metastases. Radiology. 2008 Sep;248(3):894-900.

16. Arvinda HR, Kesavadas C, Sarma PS, et. al. Glioma grading: sensitivity, specificity,
positive and negative predictive values of diffusion and perfusion imaging. J
Neurooncol. 2009 Feb 20.

17. Murakami R, Sugahara T, Nakamura H, et.al. Malignant supratentorial astrocytoma

treated with postoperative radiation therapy: prognostic value of pretreatment
quantitative diffusion-weighted MR imaging. Radiology. 2007 May;243(2):493-9.

18. Stecco A, Romano G, Negru M, et al. Whole-body diffusion-weighted magnetic

resonance imaging in the staging of oncological patients: comparison with positron
emission tomography computed tomography (PET-CT) in a pilot study. Radiol Med.
2008 Dec 11.

19. Holzapfel K, Duetsch S, Fauser C et al. Value of diffusion-weighted MR imaging in

the differentiation between benign and malignant cervical lymph nodes. Eur J Radiol.
2008 Nov 6.

20. King AD, Ahuja AT, Yeung DK, et al. Malignant cervical lymphadenopathy:
diagnostic accuracy of diffusion-weighted MR imaging. Radiology. 2007 Dec;245(3):806-
13.

21. Maeda, M., H. Kato, Sakuma H. et al. Usefulness of the apparent diffusion coefficient
in line scan diffusion-weighted imaging for distinguishing between squamous cell
carcinomas and malignant lymphomas of the head and neck. AJNR Am J Neuroradiol
2005, 26(5): 1186-92.

22. Nakayama, T., K. Yoshimitsu, Irie H. et al. Usefulness of the calculated apparent
diffusion coefficient value in the differential diagnosis of retroperitoneal masses. J Magn
Reson Imaging 2004, 20(4): 735-42.

21
23. Sumi, M., N. Sakihama, Sumi T. et al. Discrimination of metastatic cervical lymph
nodes with diffusion-weighted MR imaging in patients with head and neck cancer. AJNR
Am J Neuroradiol, 2003 24(8): 1627-34.

24. Low, R. N. and J. Gurney. Diffusion-weighted MRI (DWI) in the oncology patient:
value of breathhold DWI compared to unenhanced and gadolinium-enhanced MRI. J
Magn Reson Imaging 2007, 25(4): 848-58.

22
18. APPENDICES:
Appendix 1: Summary of Trial Procedures
Procedure Screening Post-treatment (at 4 weeks after At 6 months follow up
completion of 1st line treatment)

  At diagnosis  
 
Documentation    
 
Inclusion and exclusion criteria met X  
 
Patient registered X  
 
Signed consent form X  
 
Medical history X  
 
Investigations    
 
CT thorax, abdomen, pelvis X X X

WB diffusion-weighted MRI € X X  

FDG PET/CT scan (done routinely) X X ¥

€ Research scans
¥ If it is done clinically
Appendix 2: CRF for WB DW MR Study

Patient ID __________________________________ Initials _______________________

Time Point Lesions: 1 2 3 4 5

Baseline Site code

WB DWI
Specific location within organ

Median ADC total ((all b-values)

Date:
(mm2/s)
________
Median High ADC (b-values
>100)
(mm2/s)
Post- Median ADC total ((all b-values)
treatment WB (mm2/s)
DWI
(at 4weeks Median High ADC (b-values
post- >100)
treatment) (mm2/s)

Date:
________

Baseline scan: Stage 1 / 2 / 3 / 4 (circle one)

Post-treatment scan: Any new FDG avid lesions present since previous scan? Y / N (circle one)
Response : CR / PR / SD / PD (circle one)

Signatures: Baseline ______________________ Post-treatment _____________________

Appendix 3: CRF for WB F-18-FDG PET/CT Study

Patient ID ________________________ Initials ______________

Time Point Lesions: 1 2 3 4 5

Site code
Baseline PET/CT Specific location within organ

Date: SUVmax
________
SUV mean

SUVmax
Post-treatment
PET/CT SUV mean
(at 4weeks post-
treatment) Extent of FDG uptake (0 – 4)
Intensity of FDG uptake (0 – 4)
Date: ________ Change in FDG pattern of uptake
(0 – 3, 88)
If 88(other), please specify

Baseline Post-treatment
Score (1, 2, 3 , 4X, 4Y, 5X, 5Y)
Stage (1, 2, 3, 4)
Any new FDG avid lesions present since previous scan? (Y/N)
Is there a significant increase in overall intensity of FDG uptake in lesions
not selected for SUVmax analysis? (Y/N)
Is there a significant increase in overall extent of FDG uptake in lesions
not selected for SUVmax analysis? (Y/N)
Response (CR / PR / SD / PD)

Signatures
Appendix 4: Re-assessment CT scan final report (at 6 months following the
completion of treatment)

Patient ID ________________________ Initials ______________

Patient status at 6 months:

(tick one)

Dead Date of death____________________________

Alive with disease progression Date of progression______________

Alive with continued response

Final CT report (Please circle) CR Cru PR SD PD RD

by

1 (name)

2 (name)

Signatures:
 Appendix 5: INSTRUCTIONS FOR WB DW MRI and 18F-FDG-PET/CT
ANALYSIS

(Study Title: DWI vs FDG PET/CT in Lymphoma)

The MRI and PET-scans will be analysed visually, semiquantitatively and interpreted by
an experienced reader (the same reader should interpret all scans for each subject). A
visual assessment of the extent intensity and changes in FDG pattern of uptake will be
recorded at subsequent visits.

The same lesions (upto 5 target lesions) must be assessed on the follow up and the
same description used as at baseline/follow up scan. The presence of new lesions
should be recorded.

Lesions should be recorded in the same order at all visits.

Site codes

Nodal sites:

1 = Right cervical nodal sites (levels 1-5) 2 = Left cervical nodal sites (levels 1-5)
3 = Right axilla 4 = Left axilla
5 = Right hila 6 = Left hila
7 = Right mediastinum 8 = Left mediastinum
9 = upper retroperitoneum 10 = Lower retroperitoneam
11 = mesenteric 12 = iliac chain
13 = inguinal/femoral

Extranodal sites:

A = Head and Neck A1 Tonsils A2 Parotids A3 Salivary glands

B = Lung C = Spleen D = Liver E = Kidneys
F = Stomach G = Pancreas H = Small and large bowel
I = Skeleton/Bone marrow J = Others (please specify)

Extent of FDG uptake recorded as follows:

0 = Complete resolution
1 = Marked reduction in extent
2 = Minor reduction in extent
3 = No change in extent
4 = Increase in extent

Intensity of FDG uptake:

0 = No FDG uptake
1 = Marked reduction in intensity
2 = Minor reduction in intensity
3 = No change in intensity
4 = Increase in intensity

27
18
F-FDG PET/CT Data Analysis

PET-CT scans will be reviewed and scored by two named PET/CT specialists, who are
blinded to the patient’s clinical status. Visual and semi-quantitative interpretation will be
used. Differences in reporting will be resolved by consensus between two doctors or by
a third doctor where agreement cannot be reached.

The PET-CT response scans will be scored with reference to sites of presumed
lymphomatous involvement on the PET-CT staging scan

Negative

1 no uptake
2 uptake ≤ mediastinum
3 uptake > mediastinum but ≤ liver

NOTE if mediastinal blood pool activity is equal or greater than liver then the uptake
within the lesion should be compared with liver (lesion uptake less than liver = score 2;
lesion uptake equal to liver = score 3)

Positive

4 moderately increased uptake compared to liver at any site

5 markedly increased uptake compared to liver at any site
X new areas of uptake unlikely to be related to lymphoma

Re-assessment and FDG-PET scanning

Reassessment PET-CT scan will be done after the last cycle of chemotherapy.

FDG-PET scan is defined as positive (score 3, 4, 5) and negative (score 1, 2). The
results of this which will be scored on a 5 point scale (1 – no disease; 2 – probably no
disease; 3 – possibly disease; 4 – probably disease; 5 – definitely disease) and further
treatment will be determined according to the local protocols and practice.
FDG-PET scan positive (score 3, 4, 5)

FDG-PET scan negative (score 1, 2)

Definitions

CR - Disappearance of all evidence of disease. (a) FDG-avid or PET positive prior to

therapy; mass of any size permitted if PET negative (b) Variably FDG-avid or PET
negative; regression to normal size on CT.

PR - Regression of measuable disease and no new sites. 50% decrease in SPD of up to

6 largest dominant masses; no increase in size of other nodes (a) FDG-avid or PET
positive prior to therapy; one or more PET positive at previously involved site (b) Variably
FDG-avid or PET negative; regression on CT.

28
 SD - Failure to attain CR/PR or PD. (a) FDG-avid or PET positive prior to therapy; PET
positive at prior sites of disease and no new sites on CT or PET. (b) Variably FDG-avid
or PET negative; no change in size of previous lesions on CT.

PD - Any new lesion or increase by 50% of previously involved sites. Appearance of a

new lesion(s) > 1.5 cm in any axis, 50% increase in SPD of more than one node, or 50%
increase in longest diameter of a previously identifed node > 1 cm in short axis. Lesions
PET positive if FDG-avid lymphoma or PET positive prior to therapy.

Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission

tomography; CT, computed tomography; PR, partial remission; SPD, sum of the product of the
diameters; SD, stable disease; PD, progressive disease.

Appendix 6: INSTRUCTIONS FOR CONTRAST ENHANCED CT ANALYSIS

29
Criterium Description

Complete disappearance of all detectable disease on CT with previously

involved nodes on CT >1.5 cm in their greatest axial diameter regressing
Complete
to < 1.5 cm, and nodes of 1–1.5 cm regressing to <1 cm. In addition, resolution
response (CR)
of disease-related symptoms, normalization of biochemical abnormalities, and
normal bone marrow biopsy.

Complete
Corresponds to CR criteria, but with a residual mass >1.5 cm in greatest axial
response
diameter that has regressed by > 75% in the SPD.
unconfirmed (Cru)

At least 50% reduction in the sum of the product of the greatest diameters (SPD)
Partial response of the six largest nodes with no increase in the size of the other nodes and no
(PR) new sites of disease. Hepatic and splenic nodules should also decrease by at
least 50% in the SPD.

Stable disease
Response is less than a PR, but is not progressive disease.
(SD)

More than 50% increase in the sum of the product of the greatest diameters of
Progressive
any previously abnormal node, or appearance of any new lesions during or at
disease (PD)
the end of therapy.

Relapsed disease The appearance of any new lesion or increase in size of > 50% of previously
(RD) involved sites or nodes in patients who achieved CR or Cru.

SPD – sum of the product of the greatest diameter

Appendix 7: Patient information sheet

30
 Patient Information Sheet

Title: Pre-treatment Staging and Post-treatment Assessment in Malignant Lymphoma by Whole

Body Diffusion-weighted MR Imaging (WB-DWI) and ADC-mapping in comparison to18F-FDG
PET/CT.

Dear Sir / Madam,

You are invited to take part in a research study. Before you decide to take part it is important
that you understand why the research is being done and what it will involve. Please take time
to read the following information carefully and to discuss it with friends, relatives and others if
you wish. Please take your time to decide whether or not you wish to take part in the study. If
you need any further information or feel that anything is not clear, please ask. This copy of the
information sheet is yours to keep. Thank you for reading this.

The purpose of this study is to assess whether whole-body diffusion-weighted Magnetic Resonance
Imaging (DWI) can be used for pre-treatment and post-treatment assessment of lymphoma patients
with accuracy as good as that of the best currently available technique, PET/CT scanning. Whole-
body DWI scanning is a recently developed imaging technique which has several advantages over
PET/CT, one of the most important being that it does not involve any exposure to radiation and is also
quicker to perform.

Why have you been chosen? All patients who will receive chemotherapy as part of their treatment
for lymphoma are being asked if they would like to take part in this study.

Do you have to take part? It is entirely up to you whether or not to take part. If you decide to take
part you will be given this information sheet to keep and be asked to sign a consent form. If you
decide to take part you are still free to withdraw at any time and without giving a reason. A decision to
withdraw at anytime, or any decision not to take part, will not affect the standard of care you receive in
the future.

What will happen to you if you take part? Everyone who agrees to take part will have a whole
body Magnetic Resonance Imaging (MRI) scan before the start of treatment. This will be in addition to
the PET (Positron Emission Tomography) scan routinely performed in patients being treated for
lymphoma). The scans will be performed on the same day and we will endeavour to perform one scan
immediately following the other to minimise any inconvenience or loss of time to participants. Patients
will then undergo chemotherapy followed by a second MRI scan 4 weeks after completion of
chemotherapy. Again, this is in addition to the PET scan that is routinely performed at that time.

All participants will be reviewed in outpatients at 6 months, following the completion of their 1st line
treatment, as per routine.

What is involved in the scan?

MRI scan - MRI uses a strong magnetic field to obtain high quality images of the body in 3
dimensions. It does not require any injection. However, it is noisy and requires you to lie still whilst
having the scan performed. People who suffer from claustrophobia may feel uncomfortable having an
MRI scan performed. Please let us know if you suffer from claustrophobia.

A newer technique called diffusion-weighted MRI imaging (DWI) has been developed to gain extra

31
information about your cancer and how it is responding to treatment (this technique gives additional
information particularly about how active the cancer is in terms of how many living cells there are in
each tumour). Participants will be scanned from the top of the head to the thighs, as in a PET scan,
and this study will take approximately 20 minutes.

What are the possible benefits of taking part? We think Whole Body-Diffusion Imaging (DWI)
could be used for pre-treatment and post-treatment assessment in lymphoma patients with accuracy
as good as that of PET/CT scanning. If this is the case then the current practice of performing PET/CT
scans, which involves radiation exposure, could potentially be replaced by Whole Body-DWI, as the
latter has the advantage of being free from radiation exposure and is also quicker to perform.

What are the benefits of taking part? There is no immediate direct benefit to participants, although
the information we get from this study may help us to improve the future diagnosis, staging and
monitoring treatment response in patients with lymphoma.

Are there any side affects? No side effects of any kind are anticipated from the extra MRI study as
there is no radiation involved in this test.

Taking part in this study will be kept confidential. All information that is collected about you during
the course of this study will be kept strictly confidential. With your permission a letter will be sent
to your GP informing him/her of your participation in this study.
What will happen to the results of the research study? This may be presented in regional,
national or international meetings and maybe submitted for publication in medical journals. However,
no volunteer will be individually identified and participation in this study in no way affects future
treatment.

Who is organising and funding the research? This study has been organised by Dr. Chua and Dr.
Koh. It has been funded from the Royal College of Radiologists, Kodak Research Fellowship Funding
Scheme.

Who has reviewed the study? This study has been reviewed and approved by our local research
and ethics committee.

Contact for further information

If you have any further questions or would like to have any further information please contact Dr. SC
Chua, Consultant Radiologist on 0208 661 3544.

Thank you for reading this information sheet

Date given to patient / /

Version 4; 04 Dec 09

Appendix 8: Consent

32
Patient identification Number for this trial: _____________________________

Consent Form

Title of project: Pre-treatment Staging and Post-treatment Assessment in Malignant

Lymphoma by Whole Body Diffusion-weighted MR Imaging (WB-DWI) and ADC-mapping in
comparison to18F-FDG PET/CT.

Name of researcher: __________________________

Initial box

1. I confirm that I have read and understand the information sheet dated
_______ for the above study. I have had the opportunity to consider
the information, ask questions and have had these answered
satisfactorily.

2. I understand that my participation is voluntary and I am free to

withdraw at anytime, without giving any reason and without my
medical care or legal rights being affected.

3. I understand that relevant sections of any of my medical notes and

data collected during the study, may be looked at by responsible
individuals from Royal Marsden Hospital and the research team, from
regulatory authorities or from the NHS Trust, where it is relevant to
my taking part in this research. I give permission for these individuals
to have access to my records.

4. I agree to my GP being informed of my participation in the study.

5. I agree to records of my investigations, operations and tissue

samples to be stored and accessed by responsible individuals from
Royal Marsden Hospital and the research team, from regulatory
authorities or from the NHS Trust, where it is relevant to my taking
part in this research.

6. I agree to allow images of my scans to be stored on a databank.

Information about my treatment, pictures of the removed cancer and
images of slides to be stored on a secure database.

7. I agree to take part in the above study.

……………………….. ………………. ……………………

Patient name (print) Date Signature

33
……………………………. ………………. ……………………

Person taking consent (print) Date Signature

…………………………….. ………………. ……………………

Researcher taking consent (print) Date Signature

When completed : 1 for patient; 1 for researcher site file; 1 for medical notes

Version 4; 4 Dec 09

Appendix 9: Letter to GP

34
 Patron Her Majesty The Queen

T H E R O YA L M A R S D E N N H S F O U N D AT I O N T R U S T

L O N D O N A N D S U R R E Y

Department of Radiology
Royal Marsden Hospital
Downs Road, Sutton
Surrey SM2 5PT
Tel: +44 (0)20 8661 3544
Fax: +44 (0)20 8661 3920

Dear Dr……………………………,

Study: Pre-treatment Staging and Post-treatment Assessment in Malignant Lymphoma by

Whole Body Diffusion-weighted MR Imaging (WB-DWI) and ADC-mapping in comparison to 18F-
FDG PET/CT.

Re: Patient name:_____________________________ D.O.B.__________________

Address:_______________________________________________________________

I am writing to inform you that your patient ___________________ has kindly agreed to participate in
the above study at the Royal Marsden Hospital, after giving written informed consent.

In this trial, each participant will have two whole body MRI scans in addition to his/her routine FDG
PET/CT scans prior to and at 4 weeks after completion of their 1st line chemotherapy for lymphoma.

If you have any further questions please do not hesitate to contact us.

Yours sincerely,

35
------------------------------------------------------

Dr. Sue Chua

(Consultant in Radiology and Nuclear Medicine)

Version 4; 04 Dec 09

36