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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
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: 04/12/2009
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Investigators and contact details:
PET/CT and Radiology Investigator: Dr. Sue ChuaDepartment of Nuclear Medicine, PET and RadiologyRoyal Marsden HospitalDowns RoadSutton, Surrey SM2 5PTUnited KingdomPhone: 0208 6613544Fax: 0208 6613290e-mail: [email protected]
MRI Functional Imaging Investigator: Dr. Dow-Mu KohConsultant Radiologist (Functional Imaging),Department of RadiologyRoyal Marsden HospitalDowns RoadSutton, Surrey SM2 5PTTel: 0208 6613857Fax: 0208 6613901Email: [email protected]
PET/CT Investigator: Dr. Gary Cook Consultant in Nuclear Medicine and PETThe Royal Marsden HospitalDowns Road, Sutton, Surrey SM2 5PTTel: 208 6613921Fax: 208 6613290Email: [email protected]
PET/CT and Radiology investigator Dr. Bhuey SharmaDepartment of RadiologyRoyal Marsden HospitalDowns RoadSutton, Surrey SM2 5PTTel: 0208 6613652Fax: 0208 6613901Email: [email protected]
Radiology investigator Dr. Gina BrownDepartment of RadiologyRoyal Marsden HospitalDowns RoadSutton, Surrey SM2 5PTUnited KingdomTel: 0208 6613964Fax: 0208 6613901Email: [email protected]
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MRI Physicist Mr. David CollinsDepartment of RadiologyClinical Magnetic ResonanceRoyal Marsden HospitalDowns RoadSutton, Surrey SM2 5PTPhone:020 86613709e-mail: [email protected]
Clinical Investigator Prof. David CunninghamDepartment of MedicineRoyal Marsden HospitalDowns RoadSutton, Surrey SM2 5PTUnited KingdomPhone: 020 86613156Fax: 020 86439414e-mail: [email protected]
Clinical Investigator Dr. Ian ChauDepartment of MedicineRoyal Marsden HospitalDowns RoadSutton, SurreySM2 5PTTel: 020 86613582Fax: 020 86613890Email: [email protected]
Statistician Ms. Karen ThomasClinical Research and Development Royal Marsden HospitalDowns RoadSutton, SurreySM2 5PTTel: 0208 6613441Email: [email protected]
Trial Coordinator and Data Centre Contacts
Ms. Yvonne FoxDepartment of Nuclear Medicine Royal Marsden HospitalDowns RoadSutton, Surrey SM2 5PTUnited KingdomPhone: 0208 6613760Fax: 0208 6616761e-mail: [email protected]
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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 …………………………………………………………... 82 Background and Rationale …………………………………………………. 10
2.1 Background and Rationale for Diffusion Weighted- MR (DW-MRI) Imaging in nodal disease …………………………………………... 103 Study Hypothesis ……………………………………………………………. 114 Study Objectives ……………………………………………………………. 115 Study Design ……………………………………………………………. 12
5.1 Study flow chart …………………………………………………… 125.2 Study Methods …………………………………………………… 12
5.2.1 Study population & Method ………………………… 125.2.2 Biomarker Analysis …………………………………. 13
6 Inclusion and exclusion criteria ……………………………………………….. 146.1 Inclusion criteria ……………………………………………………. 146.2 Exclusion criteria ……………………………………………………. 156.3 Subject withdrawal criteria ………………………………… 15
7 Study Organisation …………………………………………………… 157.1 Responsibility …………………………………………………… 157.2 Risk Assessment ……………………………………………… 157.3 Trial management strategy …………………………………. 157.4 Study monitoring …………………………………………… 167.5 Data monitoring ………………………………………….. 16
8 Study Procedures ……………………………………………………………. 168.1 Recruitment …………………………………………………... 168.2 Consent ………………………………………………………. 168.3 Patient registration …………………………………………… 168.4 Subject withdrawal ……………………………………………... 178.5 Outcome reporting …………………………………………… 178.6 Premature discontinuation of the study …………………………. 17
9 Study Assessments …………………………………………………….. 1710 Statistical considerations ……………………………………………………. 1711 Ethical considerations ……………………………………………………. 18
11.1 General ethical issues …………………………………………… 1811.2 Informed consent …………………………………………… 18
12 Data Handling and Record Keeping ………………………………….. 1813 Quality Control and Quality Assurance ……………………………….…. 1914 Financing, Indemnity and Insurance …………………………………. 1915 Publication Policy …………………………………………………………... 1916 References ……………………………………………………………… 1917 Appendices ………………………………………………………………. 23
1 Summary of trial procedures …………………………………… 232 CRF for WB DW MR Study …………………………………… 24 3 CRF for WB 18F-FDG PET/CT Study …………………………. 254 Re-assessment CT scan final report …………………………. 265 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 …………………………………….. 318 Consent form ........................................................................... 329 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 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 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 sensitive for the pre-treatment 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
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routine clinical management will be eligible for the study.- Informed written consent- Willingness and ability to comply with scheduled study visits
and testsExclusion 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 exploratory
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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.
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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).
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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 aboveii) Patients with nodal or/and extranodal lesions at least 2cm in sizeiii) 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 consentv) Willingness and ability to comply with scheduled study visits and tests
6.2 Exclusion criteria
i) Pregnant or lactating ii) Concomitant uncontrolled medical conditionsiii) Poorly controlled diabetes mellitusiv) Non-FDG-avid and structurally non-measurable lesions on pre-treatment
18F-FDG-PET/CT and contrast enhanced CT respectivelyv) 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) Pregnancy4) 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
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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.
7.5Data 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 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
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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.
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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
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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-specificdatabase 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.
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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.
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.
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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.
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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.
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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 ______________
Time Point Lesions: 1 2 3 4 5
Baseline PET/CT
Date:________
Site codeSpecific location within organ
SUVmax
SUV mean
Post-treatment PET/CT
(at 4weeks post-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 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 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
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18F-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 uptake2 uptake ≤ mediastinum3 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 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 no disease; 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 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.
FDG-PET scan positive (score 3, 4, 5)
FDG-PET scan negative (score 1, 2)
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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
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Criterium Description
Complete response (CR)
Complete disappearance of all detectable disease on CT with previously involved nodes on CT >1.5 cm in their greatest axial diameter regressing to < 1.5 cm, and nodes of 1–1.5 cm regressing to <1 cm. In addition, resolution of disease-related symptoms, normalization of biochemical abnormalities, and normal bone marrow biopsy.
Complete response unconfirmed (Cru)
Corresponds to CR criteria, but with a residual mass >1.5 cm in greatest axial diameter 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 no new sites of disease. Hepatic and splenic nodules should also decrease by at least 50% in the SPD.
Stable disease (SD)
Response is less than a PR, but is not progressive disease.
Progressive disease (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 the end of therapy.
Relapsed disease (RD)
The appearance of any new lesion or increase in size of > 50% of previously 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
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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
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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 informationIf 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
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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
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……………………………. ………………. ……………………
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
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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 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 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,
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Dr. Sue Chua(Consultant in Radiology and Nuclear Medicine)
Version 4; 04 Dec 09
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