POSEIDON 01 : Etude de l’apport de l’imagerie par tomographie d’émission de positons à la 18F-FDOPA dans la proposition thérapeutique en réunion de concertation pluridisciplinaire de neuro-oncologie.

POSEIDON 01: To investigate the impact of positron emission imaging using 18F-FDOPA in neuro-oncology on therapeutic proposal during multidisciplinary case review meeting.

First name and name of coordinator :

Jacques Darcourt

Service ou département - Unit or department

Nuclear Medicine

Name and adress of the hospital

Centre Antoine Lacassagne

Phone number

04 92 03 11 47

E-mail

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Physician, dental practitioner / Biologist / Nurse, other paramedical :

Physician

Affiliated institution responsible for the budget from ministry of health

Centre Antoine LACASSAGNE

Anticipated number of recruiting centers (NC)

6

Approximate level of funding required (K euros):

185 K euros

Co-investigators (1 à n)

N°

Name

Firstname

Town

Country

Hospital

E-mail

Tel

Speciality

1

Dr BOURG

Véronique

NICE

France

CHU de Nice

Hopital Pasteur

Service de Neurologie

30, avenue de la Voie Romaine

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04.92.03.84.50

Neurology

2

Dr DE VERBIZIER LONJON

Pr DUFFAU

Delphine

Hugues

34295 Montpellier cedex 5

France

CHU de Montpellier

Hopital Lapeyronie

Medecine Nucleaire

191 Avenue Du Doyen Gaston Giraud

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04 67 33 84 64

Nuclear Medecine

Neuro-surgery

3

Dr GUEDJ

Pr CHINOT

Eric

Olivier

13385 Marseille

France

Hôpital de la Timone

Service Médecine Nucléaire
264, Rue Saint Pierre

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04 91 96 85 27

Nuclear Medecine

Neuro-surgery

4

Dr MONTRAVERS

Pr SCHLIENGER

Françoise

Michel

75020 Paris

France

Hôpital TENON

Service Médecine Nucléaire

4, rue de la Chine

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01 56 01 73 26

Nuclear Medecine

Radiation therapy

5

Dr COLLOMBIER

Dr CAMPELLO

Laurent

Chantal

30000 Nîmes

CHU de Nîmes

Service Médecine Nucléaire

Place du Pr R. Debré  

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04 66 68 32 44

Nuclear Medecine

Neuro-surgery

RATIONAL (Context and hypothesis, max 320 words)

Current treatments of high grade gliomas, involving combinations of surgery, radiation and chemotherapy have improved the overall survival during the last decade. In particular the introduction of Temozolomide in the upfront setting (Stupp et al. N Engl J Med 2005) contributed to this improvement. During the evaluation of tumour response and the follow up of the treated patients, individual decisions about change, continuation or discontinuation of treatments are proposed by the local multidisciplinary neuro-oncology board (RCP; Réunion de Concertation Pluridisciplinaire) and are usually based on MRI imaging. The new therapeutic strategies, beside their effectiveness on brain tumours, also induce effects on the surrounding tissues. These treatment-induced effects are mainly represented by radiation necrosis and pseudoprogression (vs progression) as well as pseudoresponses (vs recurrence; under anti-angiogenic treatments). They are responsible for complex MRI changes in particular on contrast enhancement which prompted the use of the new RANO criteria to cope with these phenomena (Wen et al. J Clin Oncol 2010). Furthermore, functional MRI perfusion imaging and proton magnetic spectroscopy (MRS) are routinely used to improve diagnostic accuracy. PET imaging has also shown high performances in the differential diagnosis between recurrence and post-therapeutic changes. 18F-fluoro-deoxyglucose (18FDG) can be used for glioma follow-up (Varrone et al. EJNMMI 2009). However, glial tumours exhibit specific over-expression of the amino-acid transporter LAT-1 making labelled amino-acids or analogs better suited for brain tumours PET imaging. 11C-Methionine and 18F-FET can be used, but 18F-FDOPA is currently the only one having received marketing authorization in France. It was recently showed by the UCLA group that 18F-FDOPA could change the intended management of 41% of patients with brain tumours (Walter et al. JNM 2012). The present project aims to assess the impact of 18F-FDOPA data on modifying the clinical and MRI-based initial management decision for gliomas’ patients. The study is restricted to the follow-up of treated patients with high grades gliomas.

Originality and innovative aspects (max 160 words)

18F-FDOPA PET is expensive and the measurement of its practical impact on high grade glioma patients’ management is mandatory for later medico-economical justification of its use.

One publication from the UCLA group showed a change of the intended management of 41% of patients with brain tumours (Walter et al. JNM 2012). This study had some methodological limitations: a small number of patients (58), it mixed primary tumours and recurrences, and was based on questionnaires sent to referring physicians. A specific study is needed to better assess the impact of the technique in the RCP setting

Keywords (5):

High grade gliomas, follow-up, 18F-FDOPA PET, patient management

Main objective (Detail, max 48 words)

Measure the changes induced by 18F-FDOPA results in the RCP intended management during the follow-up of patient treated for high-grades gliomas. RCP’s decisions with and without 18F-DOPA results will be compared.

Secondary objectives (detail, max 160 words)

1-    Measure the changes in the confidence level induced by 18F-FDOPA PET results when the treatment proposal is not changed.

2-    Measure the impact of 18F-FDOPA PET results in the different clinical situations: recurrence vs pseudoprogression; bevacizumab efficacy evaluation (progression vs pseudoresponse).

3-    Validate the 18F-FDOPA PET- induced modification of management (pathology when available, follow-up if not).

Primary end point (linked with the main objective)

Percentage of changes in RCP decisions induced by 18F-FDOPA PET results.

Secondary end points (linked with the secondary objectives)

1-    In patients in whom the management is not changed: percentage of variation of confidence level in the decision induced by 18F-FDOPA PET results (decreased, unchanged, increased).

2-    Percentages of changes induced by 18F-FDOPA PET results in the different clinical situations.

3-    Sensitivity, specificity, PPV and NPV of 18F-FDOPA PET results for the diagnosis of recurrence and/or progression.

Study population

Main inclusion and exclusion criteria

Patients diagnosed with high-grade glioma whose case is presented to the neuro-oncology RCP during the follow-up after the initial treatment in the following situations:
a. Diagnostic doubt between radiation necrosis and tumour progression
b. Diagnostic doubt between response and tumour progression under anti-angiogenic treatment
Inclusion criteria
- Patient with high-grade gliomas.
- Age> 18 years.

- Patient has been informed and has signed the informed consent of the study
Exclusion criteria
- Patient for whom MRI or PET-DOPA studies would be contra-indicated regarding co-morbidities or allergies.

Duration of participation of each patient (days/months/years):

 Maximum of 9 months.

Anticipated duration of recruitment (DUR) (in months):

24 months.

Total number of scheduled patients / observations to be recruited (NP) (3 digits + Justification of sample size max 80 words):

150 patients should be included.

This number is based on the assumption of a 30% change in management’s decision with a confidence interval of +/- 7.5 (formula: P+-2*√(PQ/n) which leads to 144 patients. This number is increased to 150 considering a 5% loss.

The choice of 30% is a conservative hypothesis considering the percentage of 41% published by the UCLA group (Walter et al. JNM 2012) and a local pilot study on 31 patients showing 38.5% of changes.

Number of patients / observations to be recruited / month / center ((NP/DUR)/NC) (2 digits + Justification if more than 2 patients/month/center)

Details of the study population treated in each center, according to the active file of each hospital:

Team 1 : Centre Lacassagne + CHU Nice : 20 patients/year

Team 2 : CHU Montpellier : 15 patients/year

Team 3 : HPHM Hal Timone : 25 patients/year

Team 4 : HPAP Hal Tenon : 20 patients/year

Team 5 : CHU Nimes : 30 patients/year

The potential recruitment of each center, according to these data, is between 15 to 30 per year. Recruitment will be competitive.

So, in conclusion, we can expect an average of 12 patients/observations by month that is an average of 2 patients/observations by center.

Expected number of patients eligible in the centers

N°

Name

Surname

Town

Country

Expected recruitment/month

Total

1

Pr DARCOURT

Jacques

Nice

France

1-2

40

2

Dr DE VERBIZIER LONJON

Delphine

Montpellier

France

1-2

30

3

Dr GUEDJ

Eric

Marseille

France

1-2

40

4

Dr MONTRAVERS

Françoise

Paris

France

1

24

5

Dr COLLOMBIER

Laurent

Nîmes

France

2

48

Others aspects to insure the feasibility of the project (Detail max 64 words)

Preliminarily monocentric results have been obtained and presented on 16 patients (Role of 18F-DOPA in the follow-up of brain tumours: first results. J. Darcourt et al. oral presentation at the European Conference on Clinical Neuroimaging Lille 2013).

Participating centers have experience in nuclear medicine in neurooncology and/or in 18F-FDOPA TEP.

18F-DOPA has marketing authorization in France.

Multidisciplinary neuro-oncology boards (RCP; Réunions de Concertation Pluridisciplinaire) are well structured.

Expected patient or public health benefit (Detail max 320 words)

High grade gliomas are the most common and aggressive brain tumours. The current treatments involving combinations of surgery, radiation, radiosurgery and chemotherapy have improved the overall survival of patients during the last decade (Lawrence et al Improving prognosis of glioblastoma in the 21st century: who has benefited most? Cancer 2012). Nevertheless, due to tumour recurrence, the median survival time is still limited to approximately 15 months.

In order to try to prolong the survival time on individual patients basis, multidisciplinary neuro-oncology boards (RCP; Réunions de Concertation Pluridisciplinaire) need precise diagnoses of recurrence. This is a challenging issue due the possible confounding effects of the treatments themselves (radiation necrosis and pseudoresponse). Multi-modality MR imaging (gadolinium enhancement, FLAIR sequences, proton spectroscopy, perfusion …) is constantly making progresses.

Amino-acids PET imaging is a promising technique in that context (Herholz K, Langen KJ, Schiepers C, Mountz JM. Brain tumors. Semin Nucl Med 2012). Multi-modality MR imaging and PET imaging need to be incorporated into routine post-treatment evaluation in order to improve the distinction between recurrence and treatment effects (Yang I, Aghi MK. New advances that enable identification of glioblastoma recurrence. Nat Rev Clin Oncol. 2009).

18F-FDOPA is the only 18F labelled amino-acid currently authorized in France.

However, 18F-FDOPA PET remains an expensive technique and its practical usefulness in the RCP management context needs to be specifically evaluated.

The identification of the situations in which 18F-DOPA brings added value (if any) will be useful to establish better diagnostic algorithms to improve personalized care in those patients.