Jean-Philippe Vuillez

Survival Improvement in Patients With Medullary Thyroid Carcinoma Who Undergo Pretargeted Anti–Carcinoembryonic-Antigen Radioimmunotherapy: A Collaborative Study With the French Endocrine Tumor Group

PURPOSEnNo effective therapy is currently available for the management of patients with metastatic medullary thyroid carcinoma (MTC). The efficacy of pretargeted radioimmunotherapy (pRAIT) with bispecific monoclonal antibody (BsMAb) and a iodine-131 (131I) -labeled bivalent hapten is evaluated.nnnPATIENTS AND METHODSnTwenty-nine patients with advanced, progressive MTC, as documented by short serum calcitonin doubling times (Ct DTs), received an anti-carcinoembryonic antigen (CEA)/anti-diethylenetriamine pentaacetic acid (DTPA) -indium BsMAb, followed 4 days later by a 131I-labeled bivalent hapten. Overall survival (OS) was compared with 39 contemporaneous untreated MTC patients with comparable prognostic indicators.nnnRESULTSnOS was significantly longer in high-risk, treated patients (Ct DT < 2 years) than in high-risk, untreated patients (median OS, 110 v 61 months; P < .030). Forty-seven percent of patients, defined as biologic responders by a more than 100% increase in CtDT, experienced significantly longer survival than nonresponders (median OS, 159 v 109 months; P < .035) and untreated patients (median OS, 159 v 61 months; P < .010). Treated patients with bone/bone-marrow disease had a longer survival than patients without such involvement (10-year OS, 83% v 14%; P < .023). Toxicity was mainly hematologic and related to bone/bone-marrow tumor spread.nnnCONCLUSIONnpRAIT against CEA induced long-term disease stabilization and a significantly longer survival in high-risk patients with Ct DTs less than 2 years, compared with similarly high-risk, untreated patients. Ct DT and bone-marrow involvement appear to be prognostic indicators in MTC patients who undergo pRAIT.

Fluorinated tracers for imaging cancer with positron emission tomography

Abstract2-[18F]fluoro-2-deoxy-d-glucose (FDG) is currently the only fluorinated tracer used in routine clinical positron emission tomography (PET). Fluorine-18 is considered the ideal radioisotope for PET imaging owing to the low positron energy (0.64xa0MeV), which not only limits the dose rate to the patient but also results in a relatively short range of emission in tissue, thereby providing high-resolution images. Further, the 110-min physical half-life allows for high-yield radiosynthesis, transport from the production site to the imaging site and imaging protocols that may span hours, which permits dynamic studies and assessment of potentially fairly slow metabolic processes. The synthesis of fluorinated tracers as an alternative to FDG was initially tested using nucleophilic fluorination of the molecule, as performed when radiolabelling with iodine-124 or bromide-76. However, in addition to being long, with multiple steps, this procedure is not recommended for bioactive molecules containing reactive groups such as amine or thiol groups. Radiochemical yields are also often low. More recently, radiosynthesis from prosthetic group precursors, which allows easier radiolabelling of biomolecules, has led to the development of numerous fluorinated tracers. Given the wide availability of 18F, such tracers may well develop into important routine tracers. This article is a review of the literature concerning fluorinated radiotracers recently developed and under investigation for possible PET imaging in cancer patients. Two groups can be distinguished. The first includes “generalist” tracers, i.e. tracers amenable to use in a wide variety of tumours and indications, very similar in this respect to FDG. These are tracers for non-specific cell metabolism, such as protein synthesis, amino acid transport, nucleic acid synthesis or membrane component synthesis. The second group consists of “specific” tracers for receptor expression (i.e. oestrogens or somatostatin), cell hypoxia or bone metabolism.

Effects of preoperative intentional hemodilution on the extravasation rate of albumin and fluid

OBJECTIVEnTo evaluate the effects of preoperative intentional hemodilution with 4% albumin solution on the extravasation rate of intravascular albumin and fluid in surgical patients.nnnDESIGNnA prospective, randomized, clinical study.nnnSETTINGnUniversity teaching hospital.nnnPATIENTSnTwo groups (control group [group 1] and hemodiluted group [group 2]) of 13 healthy patients were studied during a long-term (>4 hrs) surgical procedure.nnnINTERVENTIONSnAutologous technetium-99m (99mTc)-labeled red blood cells and indium-oxine ((111)In)-labeled human serum albumin were injected intravenously during anesthesia at T = 0 min in the two groups for the determination of total blood volume and albumin diffusion space, respectively. In addition, body tetrapolar electrical impedance was used to assess extracellular fluid volume. In the hemodiluted group (group 2), 15 mL/kg of blood was withdrawn over 30 mins (T = 20 mins to T = 50 mins) and simultaneously replaced by an equal volume of 4% albumin solution (0.6 g/kg).nnnMEASUREMENTS AND MAIN RESULTSnThe albumin diffusion space, the colloid oncotic pressure, the plasma albumin concentration and the electrical impedance were measured before (T = 10 mins) and after (T = 60, 120, and 240 mins) hemodilution. Urine was collected from T = 10 mins to T = 240 mins. The total blood volume was calculated at T = 10 mins. No differences in the initial values were found between the two groups. In group 2, hemodilution (hematocrit 30 +/- 3%) resulted in a steeper increase in the albumin diffusion space (p < .05) and a progressive decrease in the body electrical impedance (p < .05). The extravasation rate of albumin was 0.052 +/- 0.007 mL/kg/min in group 2 vs. 0.038 +/- 0.020 mL/kg/min in group 1 (p < .05). The value of calculated plasma volume at T = 0 min did not shown any difference between the two groups. This value was then lower than expected in group 2, corresponding to a loss of plasma volume of >3 mL/kg. Urine output was significantly lower in group 2 than in group 1 (0.7 +/- 0.4 vs. 1.4 +/- 1.0 mL/min, respectively; p < .05). A comparable decrease in colloid oncotic pressure and in plasma albumin concentration was observed in both groups.nnnCONCLUSIONSnThese results suggest that preoperative hemodilution using 4% albumin on a 1:1 volume basis for blood substitution during a prolonged surgical procedure with reduced blood losses enhances the extravasation rate of albumin and fluid to the interstitial tissues, impeding the maintenance of isovolemia. These findings support the use of a volume of infused colloid solution higher than that of withdrawn blood during preoperative hemodilution.

Chemical and Biological Evaluations of an 111In-Labeled RGD-Peptide Targeting Integrin Alpha(V) Beta(3) in a Preclinical Tumor Model

Angiogenesis plays a central role in tumor growth and metastasis. Quantification or evaluation of angiogenesis is crucial for antiangiogenic therapeutic strategies. Since integrin alpha(v)beta(3) overexpression appears specific of angiogenesis at the adult stage, it became a target of choice over the past decade, and labeled RGD-based compounds, therefore, constitute promising agents for noninvasive tumor visualization and targeting. We evaluated the chemical and biologic properties of a new tetrameric RGD-based tracer named RAFT-RGD. RAFT-RGD was radiolabeled with indium-111, using the chelating agent [(1,4,7,10-tetraazacyclododecane-N,N,N,N-tetraacetic acid] (DOTA). Labeling reaction parameters, such as time, temperature, solvent, or molar ratio, were investigated in order to optimize the final properties of the labeled RGD peptide. A 97.7% +/- 0.7% binding efficiency was achieved. (111)In-DOTA-RAFT-RGD was injected intravenously in a cohort of alpha(v)beta(3)-positive tumor-bearing nude mice. We noninvasively visualized the in vivo distribution of the tracer, using a small-animal gamma camera. In vivo distribution and stability were also studied after organ removal. In vivo, the radiolabeled peptide showed rapid blood clearance and tumor uptake. Whole-body noninvasive planar imaging allowed tumor visualization from 1 hour postinjection. However, renal uptake must be reduced to increase the therapeutic potential of RAFT-RGD.

18F-FLT and 18F-FDG positron emission tomography for the imaging of advanced well-differentiated gastro-entero-pancreatic endocrine tumours.

PurposeGastro-entero-pancreatic (GEP) endocrine tumours are a heterogenous group of tumours of variable localization and prognosis. It has been suggested that positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) may have a prognostic value and help to identify patients at risk of progression. [18F]fluoro-3′-deoxy-3′-L-fluorothymidine (18F-FLT) has been recently developed as a PET proliferation tracer. At present, there are no studies investigating its role in GEP. The aim of this prospective study was to assess the value of 18F-FLT-PET for the evaluation of GEP. Materials and methodsTen patients with biopsy-proven locally advanced or metastasized, well-differentiated GEP neuroendocrine tumours were prospectively enroled and scheduled for 18F-FDG and 18F-FLT-PET. Images were compared with other conventional diagnostic procedures, namely computed tomography, ultrasound, somatostatin receptor scintigraphy and with clinical and diagnostic follow-up. ResultsEvaluation criteria were interpreted in terms of assumed presence of tumoral tissue. According to the patients status, FDG was positive in five out of the seven patients with stable disease and in two out of the three patients with progressive disease. No positive case was identified by 18F-FLT in either the primary or the metastatic tumour site, whatever the status of patients, and this was probably a reflection of the slow proliferation rate of tumours. ConclusionThese preliminary data suggest that 18F-FLT-PET is not a suitable tracer for the evaluation of advanced well-differentiated GEP tumours. FDG showed good diagnostic performance but does not help to identify patients at risk of progression.

Can tumour marker assays be a guide in the prescription of bone scan for breast and lung cancers

Abstract. Considering the current need to improve cost-effectiveness in cancer patient management, a prospective study was undertaken in order to define the optimal combination of bone scan and tumour marker assays in breast and lung cancer strategies, as has been done in the case of prostate cancer. All patients with breast or lung cancer referred to the Nuclear Medicine Department of the Grenoble Teaching Hospital between December 1995 and April 1997 were included. A blood sample was drawn in each case for marker assay (CA15-3 or CEA and CYFRA 21-1) on the same day as the bone scan. Two hundred and seventy-five patients were included: 118 with lung cancer and 157 with breast cancer. With regard to lung cancer, no information useful for guiding bone scan prescription was obtained through CEA and CYFRA 21-1 assays. For breast cancer, the results suggest that in asymptomatic patients, a CA15-3 level of less than 25xa0U/ml (upper normal value chosen as the threshold) is strongly predictive of a negative bone scan; by contrast, high tumour marker levels are predictive of neoplastic bone involvement. When a doubtful bone scan is obtained in a patient with breast cancer, a normal marker level makes it highly probable that bone scan abnormalities are not related to malignancy.

18 F-FDG PET predicts survival after pretargeted radioimmunotherapy in patients with progressive metastatic medullary thyroid carcinoma

PurposePET is a powerful tool for assessing targeted therapy. Since 18F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated 18F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial.MethodsPatients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6xa0months, and then every 6xa0months, after pRAIT for 36xa0months. A combined evaluation was performed using anatomic, metabolic and biomarker methods. The prognostic value of the PET response was compared with demographic parameters at inclusion including age, sex, RET mutation, time from initial diagnosis, calcitonin and CEA concentrations and doubling times (DT), SUVmax, location of disease and bone marrow involvement, and with response using RECIST, biomarker concentration variation, impact on DT, and combined methods.ResultsEnrolled in the study were 25 men and 17 women with disease progression. The median OS from pRAIT was 3.7xa0years (0.2 to 6.5xa0years) and from MTC diagnosis 10.9xa0years (1.7 to 31.5xa0years). After pRAIT, PET/CT showed 1 patient with a complete response, 4 with a partial response and 24 with disease stabilization. The combined evaluation showed 20 responses. For OS from pRAIT, univariate analysis showed the prognostic value of biomarker DT (Pu2009=u20090.011) and SUVmax (Pu2009=u20090.038) calculated before pRAIT and impact on DT (Pu2009=u20090.034), RECIST (Pu2009=u20090.009), PET (Pu2009=u20090.009), and combined response (Pu2009=u20090.004) measured after pRAIT. PET had the highest predictive value with the lowest Akaike information criterion (AIC 74.26) as compared to RECIST (AIC 78.06), biomarker variation (AIC 81.94) and impact on DT (AIC 79.22). No benefit was obtained by combining the methods (AIC 78.75). This result was confirmed by the analysis of OS from MTC diagnosis.Conclusion18F-FDG PET appeared as the most potent and simplest prognostic method to predict survival in patients with progressive MTC treated with pRAIT. Biomarker DT before pRAIT also appeared as an independent prognostic factor, but no benefit was found by adding morphological and biomarker evaluation to PET assessment.

Study of inter- and intra-observer reproducibility in the interpretation of [18F]choline PET/CT examinations in patients suffering from biochemically recurrent prostate cancer following curative treatment

BackgroundThe aim of this study was to investigate the reproducibility of intra- and inter-observer interpretation of [18F]choline positron emission tomography/computed tomography examinations in patients suffering from biochemically recurrent prostate cancer following curative treatment.MethodsA total of 60 patients with biochemical recurrence after curative treatment were included in this bicentric study. The interpretations were based on a systematic analysis of several anatomic regions and all the four nuclear medicine physicians used identical result consoles. The examinations were interpreted with no knowledge of the patients clinical context. Two months later, a second interpretation of all these examinations was performed using the same method, in random order.ResultsTo evaluate local recurrences, when the prostate is in place, the results showed moderate inter- and intra-observer reproducibility: concordance of all 4 physicians has a Fleiss kappa coefficient of 0.553 with a confidence interval of (0.425 to 0.693). For patients who had had a prostatectomy, there was excellent concordance for the negative examinations. For the lymphatic basin, inter- and intra-observer reproducibility was excellent with a Fleiss kappa coefficient of 0.892 with a confidence interval of (0.788 to 0.975). The lymphatic sub-group analysis was also good. For the lymphatic groups in the right or left hemi-pelves, all Fleiss kappa and Cohens kappa coefficients are varying from 0.760 to 1 with narrow confidence intervals from (0.536 to 0.984) to (1 to 1) in favour of good/excellent inter-observer reproducibility. To evaluate bone metastasis, inter-observer reproducibility was good with a Fleiss kappa coefficient of 0.703 and a confidence interval of (0.407 to 0.881).ConclusionOur study is at time the only one on the reproducibility of interpretation of [18F]choline positron emission tomography/computed tomography examinations, which is a key examination for the treatment of patients suffering biochemical recurrence of prostate cancer. Interpretation of the [18F]choline positron emission tomography/computed tomography examination is not so useful at prostate level in patients not previously treated with prostatectomy but has a great interest on patients treated by prostatectomy. It showed good concordance in the interpretation of sub-diaphragmatic lymphatic recurrences as well as in bone metastasis.

Correlative imaging study in the diagnosis of ovarian cancer recurrences

A correlative imaging study was carried out in 61 female patients previously treated for ovarian carcinoma. Upon suspicion of recurrence, abdominopelvic immunoscintigraphy (IS) using F(ab′)2 fragments of indium-111-labelled OC 125 monoclonal antibody was performed in all patients, Ultrasonography (US) and computed tomography (CT) were performed 53 and 37 times, respectively. The diagnostic accuracy of the different imaging techniques was studied per site (abdomen and pelvis) and per patient. The diagnostic accuracy of planar scintigraphy (PS) was slightly lower than that of emission computed tomography (ECT): 66% vs 73% for abdomen, 65% vs 72% for pelvis, and 78% vs 84% in analysis per patient. The accuracy of IS (PS and ECT combined) was markedly better than that of US and CT for abdomen (IS=73%; US=30%; CT=47%), pelvis (IS=73%; US=37%; CT=52%) and analysis per patient (IS=85%; US=43%; CT =59%). The results of IS and morphological imaging techniques (MIT: US and/or CT) were correlatively analysed with the frequency of recurrence. When IS and MIT were both negative, the frequency of non-recurrence was 14/23 for abdomen, 7/12 for pelvis and 8/13 in analysis per patient. On the other hand, when both IS and MIT were positive, the frequency of recurrence was high (9/9 for abdomen, 17/21 for pelvis and 24/26 for analysis per patient). It was also found that a positive IS associated with a negative MIT was still highly suggestive of recurrence (17/21 for abdomen, 16/22 for pelvis and 17/19 for analysis per patient). The results of this study strongly suggest that 111in-labelled OC 125 IS is accurate for the diagnosis of recurrence of ovarian cancer and provides complementary data to those obtained by MIT.

Radioiodine therapy in benign thyroid disorders. Evaluation of French nuclear medicine practices

OBJECTIVESnRadioiodine is currently used routinely in the treatment of hyperthyroidism including Graves disease (GD), toxic multinodular goitre (TMNG) and toxic solitary nodule (TSN) but no consensus exists on the most appropriate way to prescribe iodine--fixed dose or calculated doses based on the gland size or turnover of (131)I. We carried out the first nationwide French survey assessing the current practices in radioiodine treatment of hyperthyroidism.nnnMATERIAL AND METHODSnA questionnaire was sent to French nuclear medicine hospital units and cancer treatment centres (n=69) about their practices in 2012.nnnRESULTSnEuthyroidism was considered the successful outcome for 33% of respondents, whereas hypothyroidism was the aim in 26% of cases. Fixed activities were the commonest therapeutic approach (60.0% of GD prescribed doses and 72.5% for TMNG and TSN), followed by calculated activities from Marinellis formula (based on a single uptake value and thyroid volume). The fixed administered dose was chosen from between 1 to 3 levels of standard doses, depending on the patient characteristics. Factors influencing this choice were disease, with a median of 370 MBq for GD and 555 MBq for TSN and TMNG, thyroid volume (59%) and uptake (52%) with (131)I or (99m)Tc. Even physicians using fixed doses performed pretherapeutic thyroid scan (98%).nnnCONCLUSIONnThis study shows that practices concerning the prescription of (131)I therapeutic doses are heterogeneous. But the current trend in France, as in Europe, is the administration of fixed doses. The study provides the baseline data for exploring the evolution of French clinical practices.