Camilo Garcia

Metastatic colorectal cancer (mCRC) may present various behaviours that define different courses of tumor evolution. There is presently no available tool designed to assess tumor aggressiveness, despite the fact that this is considered to have a major impact on patient outcome. CORIOLAN is a single-arm prospective interventional non-therapeutic study aiming mainly to assess the natural tumor metabolic progression index (TMPI) measured by serial FDG PET-CT without any intercurrent antitumor therapy as a prognostic factor for overall survival (OS) in patients with mCRC. Secondary objectives of the study aim to test the TMPI as a prognostic marker for progression-free survival (PFS), to assess the prognostic value of baseline tumor FDG uptake on PFS and OS, to compare TMPI to classical clinico-biological assessment of prognosis, and to test the prognostic value on OS and PFS of MRI-based apparent diffusion coefficient (ADC) and variation of vADC using voxel-based diffusion maps. Additionally, this study intends to identify genomic and epigenetic factors that correlate with progression of tumors and the OS of patients with mCRC. Consequently, this analysis will provide information about the signaling pathways that determine the natural and therapy-free course of the disease. Finally, it would be of great interest to investigate whether in a population of patients with mCRC, for which at present no known effective therapy is available, tumor aggressiveness is related to elevated levels of circulating tumor cells (CTCs) and to patient outcome. Tumor aggressiveness is one of the major determinants of patient outcome in advanced disease. Despite its importance, supported by findings reported in the literature of extreme outcomes for patients with mCRC treated with chemotherapy, no objective tool allows clinicians to base treatment decisions on this factor. The CORIOLAN study will characterize TMPI using FDG-PET-based metabolic imaging of patients with chemorefractory mCRC during a period of time without treatment. Results will be correlated to other assessment tools like DW-MRI, CTCs and circulating DNA, with the aim to provide usable tools in daily practice and in clinical studies in the future. NCT01591590 .

11001 Background: So far, no biomarker beyond HER2 status by immunohistochemistry (IHC) or in situ hybridization (ISH), has been validated to predict treatment efficacy of T-DM1, a novel antibody-drug conjugate targeting HER2. Zephir is a multicenter study designed to explore the role of molecular imaging in identifying patients with HER2 positive mBC (pre-treated with any number of treatment lines) unlikely to benefit from T-DM1. Here we report the results of a planned interim analysis. Methods: Fifty-two (of 105 foreseen) patients with HER2 positive BC (IHC 3+ or FISH ≥ 2.2) underwent one pre-treatment HER2 PET/CT (4 days after administration of 37 MBq zirconium-89-trastuzumab), and 3 serial FDG PET/CT: at baseline, before the 2nd cycle (early FDG), and after 3 cycles of T-DM1 (late FDG). Central standardization and validation of acquisition parameters were performed. A patient-based imaging analysis was conducted by two independent reviewers and discordances were revised by a third investigator. HER2 PET/CT was considered negative if all or the major part of the metastatic tumor load showed no or minimal tracer uptake (≤ local background). FDG PET/CT response was classified as negative if all or the major part of metastatic tumor load showed no significant metabolic response (cut-offs set at 15% for early and 30% for late FDG PET/CT). Negative and positive predictive values (NPV and PPV) of HER2 PET/CT, early FDG response, and their combination for the prediction of late FDG PET/CT response were assessed. Results: HER2 PET/CT was scored negative in 17 (32%) patients, reflecting substantial imaging heterogeneity between patients considered as HER2 positive. PPV and NPV of HER2 PET/CT, early FDG PET/CT and their combination are summarized in the Table. Conclusions: Pre-treatment HER2 imaging and early FDG response assessment after 1 cycle seem very promising in identifying patients unlikely to show a metabolic response after 3 cycles of T-DM1. Clinical trial information: NCT01565200.

385 Background: Adjuvant chemotherapy (CT) improves stage III CC outcome but is not effective for all patients (pts). PePiTA’s main hypothesis is that absence of metabolic response (MR) of the primary tumor after 1 preop CT course predicts absence of benefit from adjuvant CT (at 3-year DFS). This strategy's aim is to spare pts from useless toxicities, improve healthcare resource allocation, and guide translational research. This interim analysis was performed for safety and feasibility of MR assessment (MRA). Methods: Pts ≥ 18 years, with PS ≤ 1, diagnosed with CC considered for curative resection are eligible, after signed consent. Baseline PET is repeated after 1 CT cycle, followed by surgery. PET quality insurance and MRA are performed centrally and the result is blinded for investigators. Results: From 2010 to 2013, 114 pts—M/F (55%/45%), median age 66 (26-81), ECOG 0/1(92%/8%)—were included in 15 Belgian centers. 11 pts were excluded from analysis: 2 hyperglycemia at baseline PET; 2 withdrew consent; 6 PET-revealed stage IV CC; and 1 second cancer. Preop CT was associated with 5% grade (gr) 3-4 neutropenia, 1% gr 3 diarrhea, 1% gr 3 hypokaliemia, 1% peritonitis and 1% gr 3 thromboembolic events. Colectomies were performed in all pts after a median of 20 days (interquartile interval 18-21): 32 right (31%), 69 left (67%), and 2 procedures not detailed. Pathology showed stages 0 (1%), I (13%), II (34%), III (47%), IV (7%), without lymph node downstaging. Postoperative morbidity is 9% (95%CI 5-16%) and includes fistulas (4%), transient ischemic attack (1%), ileus (2%), and evisceration (1%), but no death. Technical or methodological reasons prevented MRA in 19/103 pts. Median SUVmax was 14.4 (4.9-47.8) at baseline, and 10.9 (0-39.3) on day 14. 2 pts presented with complete MR. For the others, median delta SUVmax was -22% (-60 to +31%). MR was observed in 60% of pts, and was absent in 40%, with equal distribution for stages II and III (p = 1.00). Conclusions: 1 course of CT is feasible before curative surgery for CC, without inducing excessive toxicity, delay or surgical morbidity. MRA indicated metabolic signs of chemoresistance in 40% of the primary tumors. Clinical trial information: NCT00994864.

Surgery is a curative treatment for patients with locally advanced colon cancer, but recurrences are frequent for those with stage III disease. FOLFOX adjuvant chemotherapy has been shown to improve recurrence-free survival and overall survival by more than 20% and is nowadays considered a standard of care. However, the vast majority of patients will not benefit from receiving cytotoxic drugs because they have either already been cured by surgery or because their tumor cells are resistant to the chemotherapy, for which predictive factors are still not available. Identifying which patients are unlikely to respond to adjuvant chemotherapy from among those who are eligible for such treatment would be a major step towards treatment personalization. It would spare such patients from unnecessary toxicities and would improve the allocation of societal healthcare resources. PePiTA is a prospective, multicenter, non-randomised trial built on the hypothesis that preoperative chemosensitivity testing using FDG-PET/CT before and after one course of FOLFOX can identify the patients who are unlikely to benefit from 6 months of adjuvant FOLFOX treatment for stage III colon cancer. The study’s primary objective is to examine the ability of PET/CT-assessed tumor FDG uptake after one course of preoperative chemotherapy to predict the outcome of adjuvant therapy, as measured by 3-year disease-free survival. Secondary objectives are to examine the predictive value of changes in PET/CT-assessed tumor FDG uptake on overall survival, to define the best cut-off value of FDG uptake for predicting treatment outcome, and to analyse the cost-effectiveness of such preoperative chemo-sensitivity testing. At study planning, exploratory translational research objectives were 1) to assess the predictive value of circulating tumor cells for disease-free survival, 2) to examine the predictive value of single nucleotide polymorphisms for disease-free survival with respect to genes related either to toxicity or to drug targets, 3) to assess genomic rearrangements associated with response or resistance to FOLFOX treatment, 4) to identify an immunologic signature associated with metabolic tumor response to FOLFOX therapy and, finally, 5) to create a bank of frozen tumor samples for future studies. PePiTA is the first study to use the primitive tumor chemosensitivity assessed by metabolic imaging as a guidance for adjuvant therapy in colon cancer. It could pave the way for tailoring the treatment and avoiding useless toxicities for the patients and inadequate expenses for the society. It could also give an interesting insight into tumoral heterogeneity, resistance to chemotherapy, genetic predisposants to oxaliplatin toxicity and immune response to cancer. 2009-011445-13 ClinicalTrials.gov number, NCT00994864

(18)F-fluoro-2-deoxy-D-glucose PET-computed tomography (CT) has a major clinical impact in oncology not only for diagnostics but also for staging, response assessment, and relapse detection. However, several other PET tracers are needed for a more complete molecular characterization of cancers which has great importance in the era of individualized targeted therapies. PET-CT is an exquisite tool for molecular imaging because it allows detection of nanomolar quantities of tracer molecules targeting different hallmarks of cancer. This article reviews the most recent findings (published in 2010-2011) on the use of molecular imaging for assessing tumour proliferation, apoptosis, growth receptor expression, bone metabolism, and hypoxia. Molecular imaging using PET-CT constitutes a major opportunity in translational research bringing fundamental molecular insights to the clinical area. Such information results invaluable for patient selection and prediction of response to therapy and serves as a crucial diagnostic tool in the era of personalized medicine.

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Résumé Les fondements de l’Action Humanitaire, au-delà de la norme légale qui est essentielle puisqu’elle entraîne des obligations inaliénables pour tous les États qui y souscrivent, sont empreints par des concepts philosophiques et politiques ancrés dans une éthique de la justice. Le contractualisme Rawlsien postule que les actions humanitaires sont basées sur l’idée qu’aider est une option noble et désirable, mais qui reste une option et pas une obligation. Peter Singer et Thomas Pogge nuancent la compréhension du devoir d’assistance. Ne pas aider serait mal et intrinsèquement équivalent à tuer. Aider n’est pas un acte caritatif digne d’éloges mais une obligation morale. Les impératifs financiers des associations, la complexité croissante des activités et le développement d’un important volet de communication entraine une professionnalisation de la médicine humanitaire. Une vision moderne de l’action humanitaire repose sur une meilleure compréhension de la justice, la solidarité et l’action globale. Pour nous donc, s’impose un ferme rapprochement éthique de l’action humanitaire avec des implications politiques claires.

A 51-year-old man presented with generalised bone pain. Initial evaluation revealed a low serum phosphorus level and elevated urinary phosphorus excretion. Aminoaciduria was normal. Standard imaging showed only minimal changes. The patient was treated with daily oral supplementation with phosphate (1 g/day) and 1,25-dihydroxyvitamin D3 (1 μg/day) to maintain euphosphataemia. In spite of the fact that this treatment was maintained for 3 years, there was no modification of renal phosphate clearance. A diagnosis of hypophosphataemic osteomalacia with renal phosphate wasting was proposed. Therefore, tumour-induced osteomalacia was suspected, triggering a diagnostic workup to find the primary tumour. These tumours are known to express somatostatin receptors, so whole body positron emission tomography (CT) imaging was performed after intravenous administration of⁶⁸Ga-DOTA-TOC (⁶⁸Ga-DOTA-D-Phe1-Tyr3-pentreotide). A solitary intense hot spot was detected in soft tissue near the right femoral internal condyle. Based on this result, curative resection of the tumour was performed.