Lymphoma DWI vs PET Protocol (Version4) 08.12.09_ for Ethics

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An Exploratory Study of Pre-treatmentStaging and Post-treatment Assessment in

Malignant Lymphoma by Whole BodyDiffusion-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

WB-DWI vs FDG PET/CT

in Lymphoma



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: 08/12/2009

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Investigators and contact details:

PET/CT and Radiology Investigator: Dr. Sue Chua

Department of Nuclear Medicine, PET and Radiology

Royal Marsden HospitalDowns Road

Sutton, Surrey SM2 5PT

United Kingdom

Phone: 0208 6613544

Fax: 0208 6613290

e-mail: [email protected] Functional Imaging Investigator: Dr. Dow-Mu Koh

Consultant Radiologist (Functional Imaging),

Department of Radiology

Royal Marsden Hospital

Downs Road


Tel: 0208 6613857

Fax: 0208 6613901

Email: [email protected]/CT Investigator: Dr. Gary Cook

Consultant in Nuclear Medicine and PET

The Royal Marsden Hospital

Downs Road, Sutton, Surrey SM2 5PT

Tel: 208 6613921

Fax: 208 6613290Email: [email protected]

PET/CT and Radiology investigator Dr. Bhuey Sharma



Downs Road


Tel: 0208 6613652

Fax: 0208 6613901

Email: [email protected]

Radiology investigator Dr. Gina BrownDepartment of Radiology


Downs Road


United Kingdom

Tel: 0208 6613964

Fax: 0208 6613901


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mailto:[email protected]












MRI Physicist Mr. David Collins


Clinical Magnetic Resonance


Downs Road


Phone:020 86613709

e-mail: [email protected] Investigator Prof. David Cunningham

Department of Medicine


Downs Road


United Kingdom

Phone: 020 86613156

Fax: 020 86439414e-mail: [email protected] Investigator Dr. Ian Chau

Department of Medicine


Downs Road

Sutton, Surrey

SM2 5PT

Tel: 020 86613582

Fax: 020 86613890


Statistician Ms. Karen ThomasClinical Research and Development


Downs Road

Sutton, Surrey

SM2 5PT

Tel: 0208 6613441

Email: [email protected] Coordinator and Data Centre

Contacts

Ms. Yvonne Fox

Department of Nuclear Medicine


Downs Road


United Kingdom

Phone: 0208 6613760

Fax: 0208 6616761

e-mail: [email protected]

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Trial Management Group

Dr Sue Chua, Dr Dow-Mu Koh, Ms Karen Thomas, Dr Gary Cook, Mr David Collins,

Professor David Cunningham, Dr Ian Chau, 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 …………………………………………... 11

3 Study Hypothesis ……………………………………………………………. 114 Study Objectives ……………………………………………………………. 12

5 Study Design ……………………………………………………………. 12

5.1 Study flow chart …………………………………………………… 12

5.2 Study Methods …………………………………………………… 13

5.2.1 Study population & Method ………………………… 13

5.2.2 Biomarker Analysis …………………………………. 13

6 Inclusion and exclusion criteria ……………………………………………….. 15

6.1 Inclusion criteria ……………………………………………………. 15

6.2 Exclusion criteria ……………………………………………………. 15

6.3 Subject withdrawal criteria ………………………………… 15

7 Study Organisation …………………………………………………… 15

7.1 Responsibility …………………………………………………… 15

7.2 Risk Assessment ……………………………………………… 16

7.3 Trial management strategy …………………………………. 16

7.4 Study monitoring …………………………………………… 16

7.5 Data monitoring ………………………………………….. 16

8 Study Procedures ……………………………………………………………. 16

8.1 Recruitment …………………………………………………... 16

8.2 Consent ………………………………………………………. 17

8.3 Patient registration …………………………………………… 17

8.4 Subject withdrawal ……………………………………………... 178.5 Outcome reporting …………………………………………… 17

8.6 Premature discontinuation of the study …………………………. 17

9 Study Assessments …………………………………………………….. 17

10 Statistical considerations ……………………………………………………. 18

11 Ethical considerations ……………………………………………………. 18

11.1 General ethical issues …………………………………………… 18

11.2 Informed consent …………………………………………… 18

12 Data Handling and Record Keeping ………………………………….. 19

13 Quality Control and Quality Assurance ……………………………….…. 19

14 Financing, Indemnity and Insurance …………………………………. 19

15 Publication Policy …………………………………………………………... 19

16 References ……………………………………………………………… 20

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

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6 Instructions for contrast enhanced CT analysis ........................... 307 Patient information sheet …………………………………….. 31

8 Consent form ........................................................................... 33

9 Letter to GP .......................................................................... 35

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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

Dates of Study

We anticipate the project will run for 12 months (start date

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 patients

25 patients in total

Primary

objectives

To prospectively assess the capability of WB-DWI with ADCmapping, 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 sensitive for the pre-treatmentstaging and post-treatment assessment of lymphoma by comparingwith reference test (18F-FDG PET/CT)positive subjects who also testpositive with WB-MRI. Both nodal and extranodal lymphomas arehighly cellular so should be readily amenable to detection by WB-DWI.

(2) To compare the ADC values of lymphoma masses before andafter treatment to determine if patients with lymphoma showingmeasurably lower pre-treatment ADC have a better response tostandard 1st line treatment; and whether effective therapy results inan ADC rise. If this is the case responders and non-respondersmight 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

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and post-treatment18F-FDG PET scans scheduled as part of 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 CTrespectively

- Contraindications to MR imaging

2. Background and Rationale

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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 promptchange 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.

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

disease

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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% respectively 18.

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 weresignificantly 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 thepotential 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

exploratory study and further studies based on larger sample sizes will be required to

test the hypothesis more robustly.

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4. Study Objectives

• Primary Objective:

To prospectively assess the capability of WB-DWI with ADC mapping, relative tointegrated fluorine-18 fluorodeoxyglucose (18 F-FDG) positron emission tomography

(PET)/computed

tomography (CT), in the pre-treatment staging and post-treatmentassessment 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

5.2.1 Study Population and Method

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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 fromprogression 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.

Primary outcome

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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).

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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 lactatingii) Concomitant uncontrolled medical conditionsiii) Poorly controlled diabetes mellitus

iv) Non-FDG-avid and structurally non-measurable lesions on pre-treatment18F-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 patient2) Patient decision to discontinue treatment3) Pregnancy

4) The development of any intercurrent medical condition which in the opinion of theinvestigator may affect patient safety, the ability to deliver treatment or the ability toassess 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 patientwill 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.

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7.2 Risk Assessment

Risk assessment of this trial has been performed with a risk assessment tool (IoP/SMAMClinical Trials Co-ordinating Committee Risk Assessment Tool) used by the RoyalMarsden 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 theframework of the Royal Marsden Hospital’s Research and Development/Ethicsmonitoring policies. All patients will be registered with the Radiology Department TrialsOffice on the day of consent or shortly afterwards.

7.5Data 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 bechecked 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

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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.

10. Statistical considerations

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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 withthe 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 thegreatest protection for the patient.

The study protocol will be given approval by the REC (Research Ethics Committee) andwill only be open to recruitment following the approval being granted. Subjects will onlybe allowed to enter the study provided they have given written informed consentfollowing a full explanation of the study and reading of the information sheet (Appendix10 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 stagewithout 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 theIndependent Ethics Committee if during the course of the study concerns about thesafety or efficacy about the proposed treatment emerge. The Principal Investigator willupdate the ethics committee of any new information relating to the trial treatment whereappropriate.

11.2 Informed consent

Written informed consent will be obtained from each patient in accordance withregulatory requirements, GCP and the Declaration of Helsinki. The subject will have theexact nature of the study explained to them (written and verbal), and the anticipatedbenefits and known side-effects. They will be advised that they are free to withdraw fromthe study without obligation. The consent form will also request permission for personnelinvolved 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 theStudy File, a copy will be put in the subject’s notes, and a copy of the signed ConsentForm 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 (Appendix12).

12. Data handling and Record Keeping

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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 thestudy. 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 RoyalMarsden Radiology Department Research Fund. The usual NHS indemnity processesare in place to cover negligent harm causes through participation in this trial. No costrequired 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.

16. References

19



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diagnostic accuracy of diffusion-weighted MR imaging. Radiology. 2007 Dec;245(3):806-

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in line scan diffusion-weighted imaging for distinguishing between squamous cell

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diffusion coefficient value in the differential diagnosis of retroperitoneal masses. J MagnReson Imaging 2004, 20(4): 735-42.

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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 completion of 1st line treatment)

At 6 months follow up

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 _______________________

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 _____________________

Time Point Lesions: 1 2 3 4 5

BaselineWB DWI

Date: ________

Site code

Specific location within organ

Median ADC total ((all b-values)(mm2/s)

Median High ADC (b-values>100)(mm2/s)

Post-treatment WB

DWI(at 4weeks

post-treatment)

Date:

________

Median ADC total ((all b-values)(mm2/s)

Median High ADC (b-values>100)(mm2/s)



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

Patient ID ________________________ Initials ______________

me Point Lesions: 1 2 3 4 5

BaselinePET/CT

Date: ________

Site codeSpecific location withinorgan

SUVmax

SUV mean

Post-treatmentPET/CT

(at 4weekspost-

treatment)

Date: ________

SUVmax

SUV mean

Extent of FDG uptake (0 –4)Intensity of FDG uptake (0– 4)Change in FDG pattern of uptake (0 – 3, 88)If 88(other), please specify

Baseline Post-treatmentScore (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 FDGuptake in lesions not selected for SUVmax analysis?(Y/N)Is there a significant increase in overall extent of FDGuptake 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 thecompletion 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). Avisual assessment of the extent intensity and changes in FDG pattern of uptake will berecorded at subsequent visits.

The same lesions (upto 5 target lesions) must be assessed on the follow up and thesame description used as at baseline/follow up scan. The presence of new lesionsshould 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 axilla5 = Right hila 6 = Left hila7 = Right mediastinum 8 = Left mediastinum9 = upper retroperitoneum 10 = Lower retroperitoneam11 = mesenteric 12 = iliac chain13 = inguinal/femoral

Extranodal sites:

A = Head and Neck A1 Tonsils A2 Parotids A3 Salivary glandsB = Lung C = Spleen D = Liver E = KidneysF = Stomach G = Pancreas H = Small and large bowelI = Skeleton/Bone marrow J = Others (please specify)

Extent of FDG uptake recorded as follows:

0 = Complete resolution1 = Marked reduction in extent2 = Minor reduction in extent3 = No change in extent4 = Increase in extent

Intensity of FDG uptake:0 = No FDG uptake1 = Marked reduction in intensity2 = Minor reduction in intensity3 = No change in intensity4 = Increase in intensity

27



18F-FDG PET/CT Data Analysis

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

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

Negative

1 no uptake2 uptake ≤ mediastinum3 uptake > mediastinum but ≤ liver

NOTE if mediastinal blood pool activity is equal or greater than liver then the uptakewithin 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 site5 markedly increased uptake compared to liver at any siteX 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 nodisease; 3 – possibly disease; 4 – probably disease; 5 – definitely disease) and further treatment will be determined according to the local protocols and practice.

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 PETnegative; 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.

FDG-PET scan positive (score 3, 4, 5)

FDG-PET scan negative (score 1, 2)

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 anew 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. LesionsPET positive if FDG-avid lymphoma or PET positive prior to therapy.

Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emissiontomography; CT, computed tomography; PR, partial remission; SPD, sum of the product of thediameters; SD, stable disease; PD, progressive disease.

Appendix 6: INSTRUCTIONS FOR CONTRAST ENHANCED CT ANALYSIS

29



Criterium Description

Completeresponse (CR)

Complete disappearance of all detectable disease on CT with previously involvednodes on CT >1.5 cm in their greatest axial diameter regressing to < 1.5 cm, andnodes of 1–1.5 cm regressing to <1 cm. In addition, resolution of disease-related

symptoms, normalization of biochemical abnormalities, and normal bone marrowbiopsy.

Completeresponseunconfirmed (Cru)

Corresponds to CR criteria, but with a residual mass >1.5 cm in greatest axialdiameter that has regressed by > 75% in the SPD.

Partial response(PR)

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

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

Progressivedisease (PD)

More than 50% increase in the sum of the product of the greatest diameters of any previously abnormal node, or appearance of any new lesions during or at theend of therapy.

Relapsed disease(RD)

The appearance of any new lesion or increase in size of > 50% of previouslyinvolved 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 1 st 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. Itdoes not require any injection. However, it is noisy and requires you to lie still whilst having the scanperformed. People who suffer from claustrophobia may feel uncomfortable having an MRI scanperformed. Please let us know if you suffer from claustrophobia.

A newer technique called diffusion-weighted MRI imaging (DWI) has been developed to gain extrainformation about your cancer and how it is responding to treatment (this technique gives additionalinformation particularly about how active the cancer is in terms of how many living cells there are in each

31



tumour). Participants will be scanned from the top of the head to the thighs, as in a PET scan, and thisstudy will take approximately 20 minutes.

What are the possible benefits of taking part? We think Whole Body-Diffusion Imaging (DWI) could beused for pre-treatment and post-treatment assessment in lymphoma patients with accuracy as good asthat 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 theadvantage 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 theinformation we get from this study may help us to improve the future diagnosis, staging and monitoringtreatment response in patients with lymphoma.

Are there any side affects? No side effects of any kind are anticipated from the extra MRI study asthere 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 FundingScheme.

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

Contact for further informationIf you have any further questions or would like to have any further information please contact Dr. SCChua, Consultant Radiologist on 0208 661 3544.

Thank you for reading this information sheet

Date given to patient / /

Version 4; 08 Dec 09

Appendix 8: Consent

Patient identification Number for this trial: _____________________________

32



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


Appendix 9: Letter to GP

34



Patron Her Majesty The Queen

THE ROYAL MARSDEN NHS FOUNDATION TRUST

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

Department of RadiologyRoyal Marsden HospitalDowns Road, SuttonSurrey SM2 5PTTel: +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 to18F-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



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Dr. Sue Chua(Consultant in Radiology and Nuclear Medicine)


Documents

Lymphoma DWI vs PET Protocol (Version4) 08.12.09_ for Ethics