Clément Bailly

State-of-the-art and recent advances in quantification for therapeutic follow-up in oncology using PET

18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET) is an important tool in oncology. Its use has greatly progressed from initial diagnosis to staging and patient monitoring. The information derived from 18F-FDG-PET allowed the development of a wide range of PET quantitative analysis techniques ranging from simple semi-quantitative methods like the standardized uptake value (SUV) to “high order metrics” that require a segmentation step and additional image processing. In this review, these methods are discussed, focusing particularly on the available methodologies that can be used in clinical trials as well as their current applications in international consensus for PET interpretation in lymphoma and solid tumors.

ImmunoPET to help stratify patients for targeted therapies and to improve drug development

Malignant tumours usually display intratumoral heterogeneity as well as phenotypic and genotypic heterogeneity among patients. Consequently, there is the need to develop treatments appropriate to each patient [1]. Screening of tumour phenotypes requires biopsy, a procedure that is invasive and limited to accessible tumour sites. Moreover, it is difficult to obtain repeated biopsies from the same lesions to explore changes in properties and heterogeneity during therapy. There is therefore the need for new noninvasive diagnostic technologies such as molecular imaging to assess whole-body tumour phenotypes to allow more specific therapeutic strategies to be developed.

The role of FDG-PET scanning in assessing lymphoma in 2012

Positron emission tomography (PET) has a proven role in the assessment diffuse large B-cell lymphoma (DLBCL) and Hodgkins lymphoma (HL). The clinical impact of PET carried out at the end of the patients course of treatment is undeniable and recommendations must be followed in the interpretation of these examinations. PET is highly recommended as part of the initial investigations of these diseases because it can be used as a reference for the interpretation at treatment completion and allows disease spread to be assessed with greater sensitivity and specificity than when computed tomography (CT) is used. It seems to be certain that PET is useful for interim examinations too, in terms of assessing prognosis in DLBCL and HL, although its impact in terms of early changes to treatment is still to be determined. The criteria for interpreting the results of these early assessments are still evolving and the annual meetings in Menton, France, of groups of experts are leading towards a uniform interpretation method. In other types of lymphoma, PET can be useful for confirming local disease staging, especially in follicular lymphoma, and for guiding biopsy in patients with low-grade lymphoma that is suspicious for transformation into more aggressive disease. Several studies are in agreement that PET is valuable for assessing prognosis at treatment completion in FL and mantle cell lymphoma, but prospective studies are needed for this new indication to be validated.

Revisiting the Robustness of PET-Based Textural Features in the Context of Multi-Centric Trials.

Purpose This study aimed to investigate the variability of textural features (TF) as a function of acquisition and reconstruction parameters within the context of multi-centric trials. Methods The robustness of 15 selected TFs were studied as a function of the number of iterations, the post-filtering level, input data noise, the reconstruction algorithm and the matrix size. A combination of several reconstruction and acquisition settings was devised to mimic multi-centric conditions. We retrospectively studied data from 26 patients enrolled in a diagnostic study that aimed to evaluate the performance of PET/CT 68Ga-DOTANOC in gastro-entero-pancreatic neuroendocrine tumors. Forty-one tumors were extracted and served as the database. The coefficient of variation (COV) or the absolute deviation (for the noise study) was derived and compared statistically with SUVmax and SUVmean results. Results The majority of investigated TFs can be used in a multi-centric context when each parameter is considered individually. The impact of voxel size and noise in the input data were predominant as only 4 TFs presented a high/intermediate robustness against SUV-based metrics (Entropy, Homogeneity, RP and ZP). When combining several reconstruction settings to mimic multi-centric conditions, most of the investigated TFs were robust enough against SUVmax except Correlation, Contrast, LGRE, LGZE and LZLGE. Conclusion Considering previously published results on either reproducibility or sensitivity against delineation approach and our findings, it is feasible to consider Homogeneity, Entropy, Dissimilarity, HGRE, HGZE and ZP as relevant for being used in multi-centric trials.

Immuno-PET for Clinical Theranostic Approaches

Recent advances in molecular characterization of tumors have allowed identification of new molecular targets on tumor cells or biomarkers. In medical practice, the identification of these biomarkers slowly but surely becomes a prerequisite before any treatment decision, leading to the concept of personalized medicine. Immuno-positron emission tomography (PET) fits perfectly with this approach. Indeed, monoclonal antibodies (mAbs) labelled with radionuclides represent promising probes for theranostic approaches, offering a non-invasive solution to assess in vivo target expression and distribution. Immuno-PET can potentially provide useful information for patient risk stratification, diagnosis, selection of targeted therapies, evaluation of response to therapy, prediction of adverse effects or for titrating doses for radioimmunotherapy. This paper reviews some aspects and recent developments in labelling methods, biological targets, and clinical data of some novel PET radiopharmaceuticals.

Radioimmunotherapy for Treatment of Acute Leukemia

Acute leukemias are characterized by accumulation of immature cells (blasts) and reduced production of healthy hematopoietic elements. According to the lineage origin, two major leukemias can be distinguished: acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Although the survival rate for pediatric ALL is close to 90%, half of the young adults with AML or ALL and approximately 90% of older patients with AML or ALL still die of their disease, raising the need for innovative therapeutic approaches. As almost all leukemic blasts express specific surface antigens, targeted immunotherapy appears to be particularly promising. However, published results of immunotherapy alone are generally modest. Radioimmunotherapy (RIT) brings additional therapeutic mechanisms using radiolabeled monoclonal antibodies (mAbs) directed to tumor antigens, thus adding radiobiological cytotoxicity to immunologic cytotoxicity. Because of the high radiosensitivity of tumor cells and the diffuse widespread nature of the disease, making it rapidly accessible to circulating radiolabeled mAbs, acute leukemias represent relevant indications for RIT. With the development of recombinant and humanized mAbs, innovative radionuclides, and more efficient radiolabeling and pretargeting techniques, RIT has significantly improved over the last 10 years. Different approaches of α and β RIT targeting CD22, CD33, CD45, or CD66 antigens have already been evaluated or are currently being developed in the treatment of acute leukemia. This review summarizes the preclinical and clinical studies demonstrating the potential of RIT in treatment of AML and ALL.

Prognostic Value and Clinical Impact of 18FDG-PET in the Management of Children with Burkitt Lymphoma after Induction Chemotherapy

Objective: Burkitt lymphoma (BL) is a rare and aggressive form of B-cell lymphoma that is curable using intensive chemotherapy. Obtaining a complete response (CR) at the end of induction chemotherapy is a major prognostic factor. This study retrospectively evaluates the potential impact of 18FDG-PET in the management of children with BL after induction chemotherapy, and the prognostic performance of the Deauville criteria. Methods: Nineteen children with BL treated according to the French LMB2001 protocol between 2005 and 2012 were included. 18FDG-PET and conventional imaging (CI) were performed after induction chemotherapy to confirm CR. 18FDG-PET was interpreted according to Deauville criteria with follow-up and/or histology as the gold standard. Results: 18FDG-PET was negative in 15 cases, in agreement with CI in 9/15 cases. The six discordant cases confirmed to be negative by histology, were considered as true negative for 18FDG-PET. Negative predictive value (NPV) of CI and 18FDG-PET were 73 and 93%, respectively. The 5-year progression-free survival (PFS) was significantly higher in patients with negative 18FDG-PET than those with positive 18FDG-PET (p = 0.011). Conclusion: 18FDG-PET interpreted using Deauville criteria can help confirm CR at the end of induction chemotherapy, with a prognostic impact on 5-year PFS. Its high NPV could limit the use of residual mass biopsy. Given the small size of our population, these results need to be confirmed by future prospective studies on a larger population.

Radioimmunoconjugates for treating cancer: recent advances and current opportunities

ABSTRACT Introduction: Radioimmunoconjugates have been used for 30 years to diagnose and treat cancer. For many years, the use of these therapeutic tools has been limited to haematological disorders, such as non-Hodgkin’s lymphoma, given that they have only had a moderate effect on solid tumours. Areas covered: Recently, several strategies have revived the potential therapeutic application for radioimmunoconjugates. In this review, the authors review the advances in immunological engineering to develop new tools like monoclonal antibodies and their derivatives. Then, the authors summarize the development of radionuclides, the use of recombinant antibodies, pretargeting approaches, and dose fractionation techniques, providing opportunities for both therapeutic and diagnostic applications. Expert opinion: Radioimmunoconjugates used in nuclear medicine have entered a new era of development. These advances give rise to a variety of opportunities in the management of various cancers, where the radiolabelled antibodies may be particularly useful in immuno-specific phenotypic imaging e.g. companion diagnostics. Concerning therapeutic applications, radioimmunoconjugates have demonstrated their efficacy in the treatment of both haematological malignancies and solid tumours. Recent procedural developments are of great interest in optimising oncological targeted therapies. In the field of cancer theranostics, we believe that radioimmunoconjugated compounds are likely to play a large part in near future.

Comparison of Immuno-PET of CD138 and PET imaging with 64 CuCl 2 and 18 F-FDG in a preclinical syngeneic model of multiple myeloma

Purpose Although recent data from the literature suggest that PET imaging with [18]-Fluorodeoxyglucose (18F-FDG) is a promising technique in multiple myeloma (MM), the development of other radiopharmaceuticals seems relevant. CD138 is currently used as a standard marker in many laboratories for the identification and purification of myeloma cells, and could be used in phenotype tumor imaging. In this study, we evaluated a 64Cu-labeled anti-CD138 murine antibody (64Cu-TE2A-9E7.4) and a metabolic tracer (64CuCl2) for PET imaging in a MM syngeneic mouse model. Experimental Design and Results 64Cu-TE2A-9E7.4 antibody and 64CuCl2 were evaluated via PET imaging and biodistribution studies in C57BL / KaLwRij mice bearing either 5T33-MM subcutaneous tumors or bone lesions. These results were compared to 18F-FDG-PET imaging. Autoradiography and histology of representative tumors were secondly conducted. In biodistribution and PET studies, 64Cu-TE2A-9E7.4 displayed good tumor uptake of subcutaneous and intra-medullary lesions, greater than that demonstrated with 18F-FDG-PET. In control experiments, only low-level, non-specific uptake of 64Cu-labeled isotype IgG was observed in tumors. Similarly, low activity concentrations of 64CuCl2 were accumulated in MM lesions. Histopathologic analysis of the immuno-PET–positive lesions revealed the presence of plasma cell infiltrates within the bone marrow. Conclusions 64Cu-labeled anti-CD138 antibody can detect subcutaneous MM tumors and bone marrow lesions with high sensitivity, outperforming 18F-FDG-PET and 64CuCl2 in this preclinical model. These data support 64Cu-anti-CD138 antibody as a specific and promising new imaging radiopharmaceutical agent in MM.

PET Imaging for Initial Staging and Therapy Assessment in Multiple Myeloma Patients

Multiple myeloma (MM) is a hematological neoplasm characterized by the clonal proliferation of malignant plasma cells in the bone marrow. MM results in diffuse or focal bone infiltration and extramedullary lesions. Over the past two decades, advances have been made with regard to the diagnosis, staging, treatment, and imaging of MM. Computed tomography (CT) and magnetic resonance imaging (MRI) are currently recommended as the most effective imaging modalities at diagnostic. Yet, recent data from the literature suggest that positron emission tomography combined with computed tomography (PET/CT) using 18F-deoxyglucose (FDG) is a promising technique for initial staging and therapeutic monitoring in this pathology. This paper reviews the recent advances as well as the potential place of a more specific radiopharmaceutical in MM.