Search

International audience; Targeted radionuclide therapy is a revolutionary tool for the treatment of highly spread metastatic cancers. Most current approaches rely on the use of vectors to deliver radionuclides to tumor cells, targeting membrane-bound cancer-specific moieties. Here, we report the embryonic navigation cue netrin-1 as an unanticipated target for vectorized radiotherapy. While netrin-1, known to be reexpressed in tumoral cells to promote cancer progression, is usually characterized as a diffusible ligand, we demonstrate here that netrin-1 is actually poorly diffusible and bound to the extracellular matrix. A therapeutic anti-netrin-1 monoclonal antibody (NP137) has been preclinically developed and was tested in various clinical trials showing an excellent safety profile. In order to provide a companion test detecting netrin-1 in solid tumors and allowing the selection of therapy-eligible patients, we used the clinical-grade NP137 agent and developed an indium-111-NODAGA-NP137 single photon emission computed tomography (SPECT) contrast agent. NP137-111 In provided specific detection of netrin-1-positive tumors with an excellent signal-to-noise ratio using SPECT/CT imaging in different mouse models. The high specificity and strong affinity of NP137 paved the way for the generation of lutetium-177-DOTA-NP137, a novel vectorized radiotherapy, which specifically accumulated in netrin-1-positive tumors. We demonstrate here, using tumor cell-engrafted mouse models and a genetically engineered mouse model, that a single systemic injection of NP137-177 Lu provides important antitumor effects and prolonged mouse survival. Together, these data support the view that NP137-111 In and NP137-177 Lu may represent original and unexplored imaging and therapeutic tools against advanced solid cancers.

We report the case of an 81-year-old man presenting with peritoneal carcinosis secondary to a metastatic castrate-resistant prostate cancer addressed for 177Lu-PSMA-1 therapy. During the second cycle, a diffuse uptake in his left forearm was observed on the 1-hour postinjection scintigraphy, typical for an accidental intra-arterial injection. Less than 24 hours postinjection, a full removal of the intra-arterial injection was observed in the man, without any pain or symptoms. Moreover, the man demonstrated an 85% PSA reduction and a CT OR following the RECIST 1.1 criteria after 3 cycles.

We reported the case of a 73-year-old man for whom a prostatic adenocarcinoma with synchronous bone metastases was diagnosed. Because his disease was progressing despite several lines of chemotherapy and hormonotherapy, he was screened with a 68Ga-PSMA PET/CT for a possible 177Lu-PSMA-617 therapy. The examination demonstrated an intense diffuse bone uptake related to the known bone involvement. It also showed an unexpected diffuse and intense lung uptake, secondary to an active polyangiitis granulomata. This intense lung uptake prohibits the radioligand therapy.

To determine efficacy and safety of thermal ablation (TA) for the local treatment of lung metastases of thyroid cancer. We retrospectively studied 47 patients from 10 centers treated by TA (radiofrequency, microwaves, and cryoablation) over 10 years. The endpoints were overall survival (OS), local efficacy, complications (CTCAE classification), and factors associated with survival. OS curves after first TA were built using the Kaplan–Meier method and compared with the log-rank test. A total of 107 lung metastases during 75 sessions were treated by radiofrequency (n = 56), microwaves (n = 9), and cryoablation (n = 10). Median follow-up time after TA was 5.2 years (0.2–13.3). OS was 93% at 2 years (95% confidence interval (CI): 86–94) and 79% at 3 years (95% CI: 66–91). On univariate and multivariate analysis with a Cox model, histology was the only significant factor for OS. OS at 3 years was 94% for follicular, oncocytic, or papillary follicular variant carcinomas, compared to 59% for papillary, medullary, insular or anaplastic carcinomas (P = 0.0001). The local control rate was 98.1% at 1 year and 94.8% at 2, 3, 4, and 5 years. Morbidity was low with no major complications (grade 4 and 5 CTCAE) and no complications in 29 of 75 sessions (38.7%). TA is a useful, safe and effective option for local treatment of lung metastases from thyroid carcinoma. Prolonged OS was obtained, especially for lung metastases from follicular, oncocytic, or papillary follicular variant carcinomas. Achieving disease control with TA delays the need for systemic treatment.

180 Background: Cabazitaxel and Lu-PSMA both improved survival in patients with mCRPC after docetaxel and an androgen receptor pathway inhibitor (ARPI), but there is limited data regarding Lu-PSMA activity after cabazitaxel. We aimed at assessing activity of Lu-PSMA and determinants of outcomes in this setting. Methods: Consecutive mCRPC patients from 6 European centers treated with Lu-PSMA after cabazitaxel were included in this retrospective study. Endpoints included radiographic progression-free survival (rPFS), time to PSA progression (PSA-TTP), PSA decline, objective response, overall survival, and safety. Results: Of 101 patients included (median age 67y), 64% had ISUP grade 4-5 disease; 71% had bone +/- nodal (LN) metastases, 22% visceral metastases, 7% LN only. All patients and 92% had received previous docetaxel and a prior ARPI (≥ 2 in 47%) before cabazitaxel respectively. Patients had received a median number of 6 cabazitaxel cycles (range 1-26). DNA damage repair alterations (DDR) were found in 11/48 (23%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (range 1-14). With a median follow-up of 5.7 months, the median rPFS from Lu-PSMA initiation was 4.3 months (m, 95%CI 3.2-5.7) and median PSA-TTP was 3.5 m (95%CI 3.0-4.5). Overall, 44 patients (44%) experienced a PSA decline ≥ 50% (PSA50), 54 (53%) ≥ 30% (PSA30), and 67 (66%) any PSA decline. Objective response rate was 34%. Baseline characteristics associated with shorter rPFS on Lu-PSMA included ISUP grade 4-5 disease (median rPFS of 3.5 vs. 7.2m, p=0.02) and a time to castration resistance < 12 months (3.1m vs. 4.5m, p=0.04). Patients with LN only had longer rPFS compared to those with bone and visceral metastases (median NR vs. 3.6 and 3.7m, respectively, p=0.02). There was no association between activity of Lu-PSMA and DNA damage repair alterations, duration of previous cabazitaxel therapy, and number of previous ARPI. During Lu-PSMA, a profound PSA decline was associated with longer rPFS: patients achieving PSA50, PSA30 or any PSA decline had respective median rPFS rates of 9.0, 8.3 and 6.2 months, while those who did not experience any PSA decline had a median rPFS of only 2.6 months. Conclusions: Lu-PSMA demonstrated substantial PSA decline but limited duration of response after cabazitaxel in a real-life setting. Adverse baseline characteristics and absence of PSA decline may help early identification of poor responders.

The number of SPECT/CT time-points is important for accurate patient dose estimation in peptide receptor radionuclide therapy. However, it may be limited by the patient's health and logistical reasons. Here, an image-based dosimetric workflow adapted to the number of SPECT/CT acquisitions available throughout the treatment cycles was proposed, taking into account patient-specific pharmacokinetics and usable in clinic for all organs at risk.Thirteen patients with neuroendocrine tumors were treated with four injections of 7.4 GBq of [Formula: see text]Lu-DOTATATE. Three SPECT/CT images were acquired during the first cycle (1H, 24H and 96H or 144H post-injection) and a single acquisition (24H) for following cycles. Absorbed doses were estimated for kidneys (LK and RK), liver (L), spleen (S), and three surrogates of bone marrow (L2 to L4, L1 to L5 and T9 to L5) that were compared. 3D dose rate distributions were computed with Monte Carlo simulations. Voxel dose rates were averaged at the organ level. The obtained Time Dose-Rate Curves (TDRC) were fitted with a tri-exponential model and time-integrated. This method modeled patient-specific uptake and clearance phases observed at cycle 1. Obtained fitting parameters were reused for the following cycles, scaled to the measure organ dose rate at 24H. An alternative methodology was proposed when some acquisitions were missing based on population average TDRC (named STP-Inter). Seven other patients with three SPECT/CT acquisitions at cycles 1 and 4 were included to estimate the uncertainty of the proposed methods.Absorbed doses (in Gy) per cycle available were: 3.1 ± 1.1 (LK), 3.4 ± 1.5 (RK), 4.5 ± 2.8 (L), 4.6 ± 1.8 (S), 0.3 ± 0.2 (bone marrow). There was a significant difference between bone marrow surrogates (L2 to L4 and L1 to L5, Wilcoxon's test: p value0.05), and while depicting very doses, all three surrogates were significantly different than dose in background (p value0.01). At cycle 1, if the acquisition at 24H is missing and approximated, medians of percentages of dose difference (PDD) compared to the initial tri-exponential function were inferior to 3.3% for all organs. For cycles with one acquisition, the median errors were smaller with a late time-point. For STP-Inter, medians of PDD were inferior to 7.7% for all volumes, but it was shown to depend on the homogeneity of TDRC.The proposed workflow allows the estimation of organ doses, including bone marrow, from a variable number of time-points acquisitions for patients treated with [Formula: see text]Lu-DOTATATE.

Prostate-specific membrane antigen (PSMA) is highly expressed on the membrane of most prostate cancer cells and to a lesser extent in normal tissues. Many vectors targeting this protein have been created over the past decade and numerous clinical studies have positively demonstrated the tolerance and efficacy of radiolabeled prostate-specific membrane antigen ligands for PSMA radioligand therapy (PRLT). Preliminary results are encouraging that PRLT will become an important addition to the current therapeutic options in a number of settings. Improvement in radiopharmaceutical targeting and combination with other oncological agents are under investigation to further improve its therapeutic efficacy. These encouraging results have led to the development of other therapies using PSMA as a target, such as PSMA–targeted chimeric antigen receptor T-cells, PSMA–targeted antibody drug conjugates, and PSMA–targeted bi-specific T-cell-directed therapy. This narrative review details the current state and advancements in prostate-specific membrane antigen targeting in prostate cancer treatment.

We reported the case of a 76-year-old man followed up since 2008 for a prostatic adenocarcinoma with pelvic and retroperitoneal nodes. He was initially treated by hormonotherapy with a good biological response. Twelve years after, he demonstrated an increased PSA level up to 10.2 ng/mL. He underwent a 68Ga-PSMA PET/CT, which shown an intense uptake by a left iliac extern mass, suspected of recurrence. The histology concluded in a hibernoma.

Positron emission tomography–computed tomography (PET/CT) combines both functional and anatomic information and provides in vivo molecular information on biological processes that can be useful at different steps of evolution of thyroid cancers. 18Fluorodeoxyglucose being highly trapped in rapidly dividing cells makes 18F-FDG-PET recommended in the staging, prognostic evaluation and follow-up of metastatic and/or of poorly differentiated thyroid carcinomas. 18F-FDG PET/CT can help in the localization of persistent/recurrent disease. However, its sensitivity depends widely on tumor burden and histology. Iodine 124 (124I) is currently under evaluation for diagnosis and pretherapeutic dosimetry planning. PET/CT using 18F-FDOPA is the most sensitive radiopharmaceutical for localizing persistent/recurrent medullary thyroid carcinoma (MTC). However, its sensitivity depends on calcitonin levels, with a threshold value of around 150 pg/mL. 18F-FDG PET/CT can also be used in MTC with short calcitonin or CEA doubling time.

International audience

TERT promoter mutations are associated with adverse clinicopathological characteristics in thyroid carcinomas and considered as a major indicator of poor outcomes. Nevertheless, most studies have pooled heterogeneous types of thyroid carcinomas and have been conducted retrospectively. We investigated the association between TERT promoter mutations and recurrence in a prospective series of 173 intermediate- to high-risk patients with thyroid cancer.Patients referred for radioiodine treatment after thyroidectomy for intermediate- to high-risk differentiated thyroid carcinoma were included in a prospective observational study and tested for TERT promoter, BRAF, and RAS mutations of their primary tumours. We analysed the relationship between TERT promoter mutations and outcomes.The prevalence of TERT promoter mutations was 20.2% (35/173) in the total population. It was significantly higher in tumours harbouring aggressive histological features (poorly differentiated carcinoma, tall cell variant of papillary cancer or widely invasive follicular cancer) than in non-aggressive tumours: 32.7% (16/49) versus 15.3% (19/124; p = 0.020). TERT promoter mutations were also strongly associated with age ≥45 years (p = 0.005), pT4 stage (p = 0.015), metastatic disease (p = 0.014), and extrathyroidal extension (p = 0.002). TERT promoter mutations were associated with poor outcomes in the total population (p 0.001) but not in the subgroup of non-metastatic patients (p = 0.051). However, they were associated with a worse outcome in patients both free of metastases and devoid of aggressive histological features. Neither BRAF nor RAS mutations were associated with event-free survival in non-metastatic patients.Although their prognostic value does not seem to overcome that of histology, TERT promoter mutations may help to better define the prognosis of localized thyroid cancer patients without aggressive histology.

Background: The benefits of post-operative radioactive iodine (RAI) administration have not been demonstrated in patients with low risk differentiated thyroid cancer (DTC). The objective of this randomized phase III trial is to assess in low risk DTC patients the non-inferiority of a follow-up strategy as compared to a systematic adjuvant post-operative RAI administration. Methods: ESTIMABL2 is a French multicentric randomized phase III trial in patients with low-risk DTC treated with total thyroidectomy with or without prophylactic neck lymph node dissection (pT1am N0 or Nx with a sum of the diameters of tumor lesions ≥ 10mm, pT1b N0 or Nx). Two to five months after surgery, in the absence of suspicious lateral neck lymph node on ultrasonography (US), patients were randomized either to the follow-up group (FU, no RAI administration) or to the ablation group and received post-operative RAI (1.1 GBq following rhTSH stimulation). Yearly controls under levothyroxine treatment consisted in thyroglobulin (Tg) and Tg antibodies (TgAb) determinations and neck-US. The primary objective was to assess at 3 years after randomization the non-inferiority of the proportion of patients without tumor-related event in the FU group as compared to the ablation group. Non-inferiority is demonstrated if the rate of patients without event at 3 years does not differ by more than ΔL=-5%. A tumor-related event was defined by the occurrence of subsequent treatment (RAI administration or surgery) for abnormal RAI uptake on the post-therapeutic WBS or by elevated Tg or TgAb levels and/or abnormal neck US during controls. Tg levels on levothyroxine treatment were considered elevated if > 2ng/mL in the FU group and > 1ng/mL in the ablation group. TgAb were considered elevated if > the upper limit range with an increase above 50% on 2 consecutive determinations performed 6 months apart. Results: 776 low-risk DTC patients were included between 2013 and 2017 in 35 French centers within the TUTHYREF network; 83% females, mean age: 52 years, papillary TC: 96%, pT1bNx: 43.6%, pT1bN0: 37.5%, pT1amNx: 12.6%, pT1amN0: 6.3%. Among the 729 patients evaluable at 3 years after randomization, tumor-related events occurred in 18/367 patients (4.9% IC95%=[2.9; 7.6]) in the FU group and in 15/362 patients (4.1% IC95%=[2.3; 6.7]) in the ablation group. Thus, 95.1% of patients in the FU group had no event at 3 years and this percentage is not inferior from the 95.9% of patients observed in the ablation group (difference = -0.8% [95% CI:-3.3%; 1.8%]. The number of subsequent surgery and/or RAI administration was 6 (1.6% IC95%=[0.6; 3.5]) in the FU group and 9 (2.5% IC95%=[1.1; 4.7]) in the ablation group. Conclusion: this phase III trial demonstrates the non-inferiority of a follow-up strategy compared to a systematic adjuvant post-operative administration of RAI (1.1GBq following rhTSH) in low risk DTC patients (PHRC 2012; NCT01837745).

Introduction La RIV des TE avec du 177Lu DOTATATE est d’une efficacite remarquable. L’Agence Europeenne du Medicament recommande une surveillance renforcee. Selon les etudes, 2 a 10 % des patients auront des effets secondaires graves, hematologiques. On connait les limites pour l’extrapolation de ces resultats dans la vraie vie et nous n’avons pas de facteurs predictifs clairement identifies a ce jour. L’utilisation du 177Lu DOTATATE requiert donc une vigilance et une formation des praticiens. En outre, les TE sont des maladies heterogenes. Pour certaines formes avancees, mais lentement evolutives, la question du rapport benefice-risque du traitement se pose. Les connaissances radiobiologiques sont moins etoffees pour la RIV que pour la radiotherapie externe. Il est donc necessaire d’approfondir la recherche dans ce domaine. Comment allier evaluation dans la vraie vie, encadrement de pratiques, tout en favorisant la recherche ? Methode Nous proposons de creer un registre qui se distingue d’une base de donnees et d’une cohorte par un recueil exhaustif, non biaise et non limite dans le temps. Avec le soutien de la SFMN, du CNP de medecine nucleaire et le support technique et juridique de la Federation des Specialites Medicales, nous avons cree le registre Epilunet (Epidemiologie-Lutetium-NeuroEndocrine-Tumor). Il s’inspire du registre Epithor qui, avec des milliers de procedures de chirurgie thoracique enregistrees, ameliore la securite des soins, participe a la formation medicale (reconnue par l’HAS), tout en permettant une valorisation scientifique et economique des donnees. Resultats Epilunet est reconnu par la CNIL. La saisie, assistee par des menus deroulants, permet une ouverture rapide des dossiers qui sont compiles via internet dans un registre national. Chaque centre disposera de l’acces a ses donnees. L’utilisation de la base nationale pour des projets de recherche sera possible sur accord du comite scientifique (a condition de citer l’origine). Discussion–conclusion Ce registre pourrait prefigurer celui pour la 177Lu PSMA therapie. Nos confreres espagnols publient deja les resultats dans la vraie-vie de 125 patients inclus dans leur registre national (SEPTRALU Registry). Si, et seulement si, Epilunet est renseigne de maniere exhaustive et reguliere, alors nous pourrons savoir quels malades nous traitons, pour quel benefice et avec quelle toxicite ? Le defi collectif est donc de parvenir a remplir ce registre ; y arriverons-nous. ?

Elderspeak is often used when talking to older individuals and is characterised by a slower and/or louder speech, a patronising tone, etc. A part of the reason of such communication can be found in the actual context of negative view of ageing. However, the link between view of ageing and elderspeak has never been objectively studied in oncology. Therefore, 40 healthcare professionals (physicians and medical students) record a podcast where they have to explain an endocrine therapy to two fictional patients (40- vs. 70-year old). Results show that when participants explained the treatment to the older patient, they used shorter utterances and made more repetitions. They also evoked fewer side effects such as sexual issues. Moreover, reduction in length of utterances and of word-per-minute rate was observed for older patient when participants have a positive view of ageing but for both patients when they have a negative view of ageing. In conclusion, physicians and medical students used elderspeak when they explained a treatment to older patients. Participants with a more negative view of ageing also unconsciously talked slower and made shorter utterances to a 40 -year-old patient.

Many studies have reported the high performance of 6-fluorine-18-fluorodihydroxyphenilalanine (F-FDOPA) PET/CT in the diagnosis of pheochromocytomas but nobody seems to have investigated physiological and pathological adrenal glands from a quantitative point of view. The purpose of the present study was to assess the quantitative F-FDOPA uptake of normal and pathologic adrenal glands and to establish thresholds to characterize pheochromocytomas. We were especially interested in characterizing the remaining adrenal glands captation after an adrenalectomy.We reviewed 112 F-FDOPA PET/CT scans taken for different indications. A total of 212 adrenal glands, of which 17 were pheochromocytomas, were analyzed on the basis of their functional and morphological features. The final diagnosis was based on histologic proof when available (six pheochromocytomas) or after synthesis of clinical, biological, morphological, and functional results. Maximum standardized uptake value (SUVmax), mediastinum, and liver ratios in case of pheochromocytomas, adenomas, and solitary adrenal glands were determined and compared with those of healthy glands. Receiver operating characteristic curves were determined and areas under the curve were compared for different cutoffs of each index.Pheochromocytomas demonstrated a higher F-FDOPA uptake compared with normal adrenal glands (mean SUVmax: 7.5, SD 4.0, range: 3.5-20.0 vs. mean SUVmax: 2.6, SD: 0.8, range: 1.0-6.9) (P0.0001). An SUVmax threshold of 4.2 has a sensitivity and specificity of 94 and 98%, respectively. The areas under the curve were 0.988, 0.991, and 0.987 for an SUVmax of 4.2, a mediastinum ratio of 3.0, and a liver ratio of 1.7, respectively. A large number of nonsecreting pheochromocytomas were noticed. On the basis of the SUVmax no statistically significant difference was found between secreting (SUVmax: 8.9, SD: 5.3) and nonsecreting pheochromocytomas (SUVmax: 5.1, SD: 0.9) (P=0.141). After unilateral adrenalectomy, solitary glands presented no increased uptake compared with healthy adrenal glands. An unexpected lower captation was also observed (SUVmax: 2.0, P=0.047).We confirm the high affinity of F-FDOPA for secreting or nonsecreting pheochromocytoma. Indeed within a series of various adrenal glands, only these tumors presented a significant increased uptake compared with normal adrenal glands. Because of a high rate of nonhypersecreting lesions, F-FDOPA can act as a surrogate to biological assays. After an adrenalectomy, the remaining glands did not demonstrate compensatory accumulation of F-FDOPA. To our knowledge this last point has never been addressed.

International audience

Background The prognosis of poorly differentiated thyroid carcinomas (PDTC) is heterogeneous though generally poor. The objectives of this study were to identify clinical and molecular factors of poor prognosis. Methods One hundred four consecutive patients treated for a PDTC between 01/01/2000 and 31/12/2010 were included in this study. A pathological review was done for all cases (blinded to clinical data and outcome). Results All patients underwent thyroidectomy. Adjuvant radioactive-iodine was administered in 95.2% of them. Tumours were pT3 or pT4 in 68.3% of cases and metastatic in 38.5% of patients. Extrathyroidal extension (ETE) was observed in 40% of patients. At the end of the initial treatment, only 37% of patients were considered in remission. Fifty-two patients (50%) became refractory to radioiodine during follow-up. The 5-year overall survival was 72.8% and the 5-year recurrence-free survival (RFS) was 45.3%. Remission after initial treatment was an independent factor of RFS (HR = 0.22; [0.10–0.49]). ETE was the only significant parameter influencing the overall survival in multivariate analysis. TERT promoter mutations at positions −124 (C228T) and −146 (C250T) were present in 38.1% of analysed patients and significantly associated with radioiodine resistance but not with overall survival. Half of TERT promoter mutant tumours harboured also RAS or BRAF mutations. Conclusion PDTC form a heterogeneous group of patients with usual late-stage diagnosis, low radioactive iodine avidity and frequent metastatic spread. TERT promoter mutations could help to identify patients with high risk of radio-iodine refractoriness.

F-FDOPA is a well-established tool to explore pheochromocytomas. It tends to replace I-MIBG scan in metastatic pheochromocytomas, multiple endocrine neoplasia type 2-related tumors, succinate dehydrogenase [ubiquinone] iron-sulfur subunit-negative tumors, and succinate dehydrogenase[ZERO WIDTH SPACE]-positive lesions. To our knowledge, no study has characterized physiological and pathological adrenal glands with F-FDOPA from a quantitative point of view. We report the features of different normal and pathological adrenal glands with F-FDOPA. Within our series, only pheochromocytomas present a significantly increased uptake reflecting the high specificity of this tracer. Tumors such as adenomas or myelolipomas present no F-FDOPA significant accumulation. Interestingly, adrenal gland hyperplasia and solitary glands do not demonstrate compensatory uptake.

ObjectiveTyrosine kinase inhibitors (TKIs) are used to treat patients with advanced thyroid cancers. We retrospectively investigated the efficacy of TKIs administered outside of clinical trials in metastatic sites or locally advanced thyroid cancer patients from five French oncology centers.Design and methodsThere were 62 patients (37 men, mean age: 61 years) treated with sorafenib (62%), sunitinib (22%), and vandetanib (16%) outside of clinical trials; 22 had papillary, five had follicular, five had Hürthle cell, 13 had poorly differentiated, and 17 had medullary thyroid carcinoma (MTC). Thirty-three, 25, and four patients were treated with one, two, and three lines of TKIs respectively. Primary endpoints were objective tumor response rate and progression-free survival (PFS). Sequential treatments and tumor response according to metastatic sites were secondary endpoints.ResultsAmong the 39 sorafenib and 12 sunitinib treatments in differentiated thyroid carcinoma (DTC) patients, partial response (PR) rate was 15 and 8% respectively. In the 11 MTC patients treated with vandetanib, 36% had PR. Median PFS was similar in second-line compared with first-line sorafenib or sunitinib therapy (6.7 vs 7.0 months) in DTC patients, but there was no PR with second- and third-line treatments. Bone and pleural lesions were the most refractory sites to treatment.ConclusionsThis is the largest retrospective study evaluating TKI therapies outside of clinical trials. DTC patients treated with second-line therapy had stable disease as best response, but had a similar median PFS compared with the first-line treatment.

Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer with a poor prognosis. Locoregional staging is based on dynamic contrast-enhanced (DCE) CT or MRI. The aim of this study was to compare the performances of FDG PET/CT and DCE CT in locoregional staging of IBC and to assess their respective prognostic values. The study group comprised 50 women (median age: 51 ± 11 years) followed in our institution for IBC who underwent FDG PET/CT and DCE CT scans (median interval 5 ± 9 days). CT enhancement parameters were net maximal enhancement, net early enhancement and perfusion. The PET/CT scans showed intense FDG uptake in all primary tumours. Concordance rate between PET/CT and DCE CT for breast tumour localization was 92 %. No significant correlation was found between SUVmax and CT enhancement parameters in primary tumours (p > 0.6). PET/CT and DCE CT results were poorly correlated for skin infiltration (kappa = 0.19). Ipsilateral foci of increased axillary FDG uptake were found in 47 patients (median SUV: 7.9 ± 5.4), whereas enlarged axillary lymph nodes were observed on DCE CT in 43 patients. Results for axillary node involvement were fairly well correlated (kappa = 0.55). Nineteen patients (38 %) were found to be metastatic on PET/CT scan with a significant shorter progression-free survival than patients without distant lesions (p = 0.01). In the primary tumour, no statistically significant difference was observed between high and moderate tumour FDG uptake on survival, using an SUVmax cut-off of 5 (p = 0.7 and 0.9), or between high and low tumour enhancement on DCE CT (p > 0.8). FDG PET/CT imaging provided additional information concerning locoregional involvement to that provided by DCE CT on and allowed detection of distant metastases in the same whole-body procedure. Tumour FDG uptake or CT enhancement parameters were not correlated and were not found to have any prognostic value.

Hybrid systems associating the sharpness of anatomic images coming from computed tomography (CT) and radionuclide functional imaging (SPET or PET) are opening a new era in oncology. This multimodal imaging method is now routinely used for the diagnosis, extent, follow up, treatment response and detection of occult disease in different types of malignancies with a significant impact on the treatment strategy leading for a change for more than 68% of all investigated patients.

BACKGROUND: Breast cancer recurrence is often suspected on tumor marker rising in asymptomatic patients. The value of fluorine-18 fluorodeoxyglucose (18FDG)–positron emission tomography/computed tomography (PET/CT) imaging to detect recurrence and its subsequent impact on patient management were retrospectively assessed. METHODS: PET/CT scans were performed on 228 asymptomatic patients (mean, 60.8 years; range, 30-91 years) presenting with rising CA 15-3 and/or CEA serum levels. RESULTS: PET/CT scans were positive in 181 patients (79.5%) and normal in 47 patients, whereas 187 true recurrences were diagnosed. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT imaging for detection of breast cancer recurrence were 93.6%, 85.4%, 96.7%, 74.5%, and 92.1%, respectively. When compared with the standard workup available in 67 patients, PET/CT imaging had a higher sensitivity and accuracy (94.5% vs 33% and 94% vs 48%, respectively). Recurrences were confirmed by pathology, conventional imaging techniques, or radiological and clinical follow-up beyond 1 year (mean, 34 months; range, 12-67 years) in 32, 130, and 25 patients, respectively. The diagnosis of recurrence led to a treatment modification in 123 patients (54%). CONCLUSIONS: 18FDG-PET/CT imaging is an efficient technique to detect breast cancer recurrence suspected on tumor marker rising in asymptomatic patients. It may thus contribute to improve patient management, providing an earlier diagnosis with complete whole-body staging as a “one-stop shop” procedure. Cancer 2011. © 2010 American Cancer Society.

Resume Cette observation montre l’interet de la TEP/TDM au FDG dans la caracterisation de tumeurs mammaires bilaterales chez une femme jeune sans facteur de risque carcinologique.

Purpose: Because calcitonin level remains elevated after initial treatment in many medullary thyroid carcinoma (MTC) patients without evidence of disease in the usual imaging work-up, there is a need to define optimal imaging procedures. Patients and Methods: Fifty-five consecutive elevated calcitonin level MTC patients were enrolled to undergo neck and abdomen ultrasonography (US); neck, chest, and abdomen spiral computed tomography (CT); liver and whole-body magnetic resonance imaging (MRI); bone scintigraphy; and 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/CT scan (PET). Results: Fifty patients underwent neck US, CT, and PET, and neck recurrence was demonstrated in 56, 42, and 32%, respectively. Lung and mediastinum lymph node metastases in the 55 patients were demonstrated in 35 and 31% by CT and in 15 and 20% by PET. Liver imaging with MRI, CT, US, and PET in 41 patients showed liver in 49, 44, 41, and 27% patients, respectively. Bone metastases in 55 patients were demonstrated in 35% by PET, 40% by bone scintigraphy, and 40% by MRI; bone scintigraphy was complementary with MRI for axial lesions but superior for the detection of peripheral lesions. Ten patients had no imaged tumor site despite elevated calcitonin level (median 196 pg/ml; range 39–816). FDG uptake in neoplastic foci was higher in progressive patients but with a considerable overlap with stable ones. Conclusion: The most efficient imaging work-up for depicting MTC tumor sites would consist of a neck US, chest CT, liver MRI, bone scintigraphy, and axial skeleton MRI. FDG PET scan appeared to be less sensitive and of low prognostic value.

Whether mutation status should be used to guide therapy is an important issue in many cancers. We correlated mutation profile in radioiodine-refractory (RAIR) metastatic thyroid cancers (TCs) with patient outcome and response to tyrosine kinase inhibitors (TKIs), and discussed the results with other published data. Outcome in 82 consecutive patients with metastatic RAIR thyroid carcinoma prospectively tested for BRAF, RAS and PI3KCA mutations was retrospectively analyzed, including 55 patients treated with multikinase inhibitors. Papillary thyroid carcinomas (PTCs) were the most frequent histological subtype (54.9 %), followed by poorly differentiated thyroid carcinoma [PDTC] (30.5 %) and follicular thyroid carcinoma [FTC] (14.6 %). A genetic mutation was identified in 23 patients (28 %) and BRAF was the most frequently mutated gene (23 %). Median progression-free survival (PFS) on first-line TKI treatment was 14.6 months (95% CI 9.9–18.4). BRAF mutation positively influenced median PFS, both in the entire TKI-treated cohort (median PFS 34.7 months versus 11.6 months; hazard ratio [HR] 0.29; 95% CI 0.09–0.98; p = 0.03) and in the TKI-treated PTC cohort (n = 22) [log-rank p = 0.086; HR 2.95; 95 % CI 0.81–10.70). However, in TKI-treated patients, PDTC histologic subtype was the only independent prognostic factor for PFS identified in the multivariate analysis (HR 2.36; 95% CI 1.01–5.54; p = 0.048). Patients with BRAF-mutant PTC had a significantly longer PFS than BRAF wild-type when treated with TKIs. However, due to the small number of BRAF-mutant patients, further investigations are required, especially to understand the potential positive effect of BRAF mutations in RAIR TC patients while having a negative prognostic impact in RAI-sensitive PTC patients.

Objectifs Le pheochromocytome (PHEO) est une complication survenant chez 0,1 a 5,7 % des patients presentant une neurofibromatose de type 1 (NF1). Selon les recommandations, il n’est recherche qu’en cas de symptomes evocateurs. Cependant, certaines publications font etat de formes asymptomatiques, voire de tumeurs non secretantes. La prevalence de cette tumeur classiquement de 1 % est peut-etre sous-estimee. L’objectif de l’etude est d’evaluer sur une grande serie la prevalence du PHEO dans cette population. Materiels et methodes Etude prospective monocentrique avec inclusion consecutive de tous les patients de plus de 18 ans consultant pour NF1 a partir de janvier 2014. Apres accord du patient, sont recueillies les donnees cliniques en particulier la tension arterielle et la recherche de symptomes evocateurs. Il est realise systematiquement une imagerie standard (scanner abdominal ou, si refus, echographie abdominale) et dosage des derives methoxyles urinaires. En cas de positivite des deux examens ou de l’imagerie, une scintigraphie a la 18F-DOPA (ou MIBG-123I) etait realisee. Le diagnostic de PHEO secretant (PHEO-S) est retenu si scintigraphie positive et derives methoxyles eleves ; non secretant (PHEO-NS) en cas de scintigraphie positive et de derives normaux. Resultats Entre janvier 2014 et aout 2015, 234 patients ont ete inclus. Cent cinquante-six patients (66,7 %) ont realise le dosage et l’imagerie standard. Trente-huit patients n’ont realise aucun examen. Sur ces 156 patients, 12 PHEO ont ete diagnostiques, soit une prevalence de 7,7 %, incluant 6 PHEO-S ne se traduisant cliniquement que chez 2 patients par une HTA. La taille des lesions surrenaliennes etait plus importante que chez les patients presentant un PHEO-NS (25,2 ± 6,6 versus 14 ± 6,9 mm, p = 0,0165) ; la metanephrine et la normetanephrine etaient 3,2 ± 2,6 N et 2,8 ± 1 N, respectivement. Seulement les PHEO-S et les PHEO-NS mais avec une lesion de plus de 2 cm etaient operes. Les 4 patients operes avaient des lesions intrasurrenaliennes presentant au moins un critere d’agressivite anatomopathologique. Conclusions Cette etude, la plus grande a ce jour sur le sujet, montre que la prevalence du PHEO dans la NF1 est de 7,7 % et non de 1 %. La frequente absence de traduction clinique des lesions secretantes doit faire revoir la strategie actuelle de n’explorer que les patients symptomatiques, afin de ne pas faire courir aux patients les risques inherents a l’existence de PHEO meconnus.

11054 Background: Advanced SyS are rare tumors with limited curative options. FZD10 is highly expressed in SyS but not in normal adult tissue. OTSA101 is a MAb targeting FZD10, labelled with a radioisotope. Methods: We conducted a phase I, FIH study including adult pts with advanced, refractory SyS. In part 1, pts received OTSA101 labelled with In111 used as radiotracer to assess biodistribution and tumor uptake. In part 2, pts with significant tumor uptake were randomized to receive OTSA101 labelled with 370MBq of Y90 (Arm A) or 1110MBq Y90 (Arm B). Primary endpoints were occurrence of unacceptable biodistribution /lack of tumor uptake in part 1 and occurrence of related adverse events (AEs) Grade ≥ 3 during the first 8 weeks following injection of Y90OTSA101 in part 2. Responses were assessed per RECIST 1.1. Results: From January 2012 to June 2015, 20 pts (10 females, median age 43, range 21-67) with advanced SyS were enrolled. Ten pts (50%) had sufficient tumor uptake to proceed to part 2 and 8 were randomized (Arm A: 3 and Arm B: 5). Two pts were not randomized due to worsening PS. During part 2, the most common Grade ≥ 3 AEs were haematological, including reversible lymphopenia, thrombocytopenia and neutropenia, and were more common in Arm B. One pt with SD after 12 weeks received a 2nd injection of 90Y-OTSA101, but experienced fatal hemoptysis. No objective response was observed. Best response was SD in 5/8 pts lasting up to 21 weeks for 1 pt. Conclusions: This FIH shows that radioimmunotherapy targeting FZD10 is feasible and safe in SyS pts. Tumor uptake was heterogeneous but sufficient to select 50% of pts for 90Y-OTSA101 treatment. Due to limited sample size, further clinical investigations are needed to assess the therapeutic activity of 90Y-OTSA101 with a recommended dose of 1110MBq of 90Y. Clinical trial information: NCT01469975.

The aim of this analysis was to evaluate a new visual scoring scale developed to facilitate the qualitative appraisal of lesion uptake on (18)F-fluorothymidine PET ((18)F-FLT-PET).Sixty-two patients with a pulmonary lesion of unknown aetiology who had undergone an F-fluorodeoxyglucose-PET/computed tomography (CT) suspicious for malignancy prospectively underwent an (18)F-FLT-PET/CT. Three nuclear medicine physicians independently reviewed each (18)F-FLT-PET/CT scan with knowledge of the location of the pulmonary lesion but blinded to the final diagnosis. They scored the lesion (18)F-FLT uptake as follows: (0) no visible uptake; (1)spleen; (2) ≥ spleen, butboth liver and marrow; (3) between liver and marrow; (4)liver andmarrow. Lesion mean (SUV(mean)) and maximum (SUV(max)) standardized uptake values were measured in a separate session.In all, 35 lesions were malignant and 27 were benign, as assessed on the basis of surgery, biopsy or follow-up of at least 12 months. Visual score, SUV(mean) and SUV(max) were statistically different between benign and malignant lesions. The visual scoring scale showed substantial to almost-perfect interobserver agreement with a weighted κ value of 0.84, 0.67 and 0.65 for each observer pair. The visual score was highly correlated to SUV(mean) and SUV(max) (r=0.83 and 0.87, respectively) and described a logarithmic pattern in relation to SUV(mean) and SUV(max) (r =0.67 and 0.72, respectively). The area under the receiver-operating characteristic curve for the visual score was 0.86 and was statistically different from that for SUV(mean) (0.77; P=0.026) and SUV(max) (0.79; P=0.047).The (18)F-FLT scoring scale we propose is easy to use with high interobserver agreement and a significantly better discriminative capacity compared with SUV measurements. It has the potential to harmonize the qualitative interpretation of (18)F-FLT-PET/CT in lung cancer diagnosis.

Objectifs Il existe un metabolisme physiologique visualisable en TEP a la 18F-DOPA des glandes surrenales (integration dans la chaine de synthese des catecholamines). La semi-quantification en TEP/TDM a la 18F-DOPA (avec l’obstacle methodologique de la quantification du SUV sur de petites zones), peut-elle apporter des arguments en faveur du caractere simplement physiologique de cette fixation ou orienter vers une pathologie surrenalienne (adenome, pheochromocytome benin ou malin…), de facon independante, ou en s’integrant dans un cadre plus documente, comportant des explorations radiologiques et biologiques dediees ? Qu’en est-il de la fixation sur la surrenale restante apres surrenalectomie unilaterale ? Quelle attitude adopter en cas de fixation inhabituelle observee incidemment ? Materiels et methodes Nous avons analyse retrospectivement, sur 94 examens consecutifs TEP/TDM a la 18F-DOPA (2,5 MBq/kg) realises dans notre centre entre 2014 et 2015 (indications variees), les surrenales (etudiees : n = 171) selon leur morphologie, la captation du traceur sur les acquisitions tardive (50 min apres injection) et precoce (a 10 min, si realisee,) et calcule les rapports SUXmax surrenalien/bruit de fond hepatique (Rh) et surrenalien/surrenale controlaterale (Rs). Une ROI de 20 mL etait placee dans le segment VIII hepatique en excluant l’elimination biliaire. Les ROI surrenaliennes etaient tracees au niveau du foyer surrenalien le plus fixant, sur la lesion surrenalienne eventuelle. Des mesures bidimensionnelles des nodules et des surrenales saines ont ete realisees. Resultats Sur les 171 surrenales etudiees au temps tardif : 21 surrenales nodulaires, 6 presentes mais non mesurables, aucune hyperplasie et 6 antecedents de surrenalectomie unilaterale. Pour les surrenales normales morphologiquement (n = 144, diametre min 6 mm) : Rh : M 1,03 ; SD 0,33 (0,4–2,7) Rs : M 1,25, SD 0,24. Pour les 6 surrenales uniques, Rh : M 0,8 ; SD 0,4 (0,4–1,6). La fixation n’etait pas augmentee (pas de captation compensatrice). Pour les surrenales nodulaires : n = 21 (DMax 30 mm), Rh : M 1,69 ; SD 1,29 (0,4–8,0) dont 8 > 2,7 (26 %), comprenant 5 pheochromocytomes confirmes : Rh : M 5,1 ; SD 1,9 (3,4–8) ; Rs : M 2,2 ; SD 1,9 (1,1–5), 1 myelolipome peu fixant : Rh 0,9 et 3 adenomes (evoques radiologiquement) Rh Conclusions Dans cette serie, l’intensite de fixation en 18F-DOPA apparait tres augmentee pour les pheochromocytomes (secretants ou non), pas de captation compensatrice des surrenales uniques. Un plus grand panel permettra l’etablissement d’une borne superieure de fixation physiologique, de conforter statistiquement ces premieres orientations, importantes a prendre en compte en cas d’anomalie fortuite.

Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer with a poor prognosis. Locoregional staging is based on dynamic contrast-enhanced (DCE) CT or MRI. The aim of this study was to compare the performances of FDG PET/CT and DCE CT in locoregional staging of IBC and to assess their respective prognostic values.The study group comprised 50 women (median age: 51 ± 11 years) followed in our institution for IBC who underwent FDG PET/CT and DCE CT scans (median interval 5 ± 9 days). CT enhancement parameters were net maximal enhancement, net early enhancement and perfusion.The PET/CT scans showed intense FDG uptake in all primary tumours. Concordance rate between PET/CT and DCE CT for breast tumour localization was 92%. No significant correlation was found between SUVmax and CT enhancement parameters in primary tumours (p0.6). PET/CT and DCE CT results were poorly correlated for skin infiltration (kappa = 0.19). Ipsilateral foci of increased axillary FDG uptake were found in 47 patients (median SUV: 7.9 ± 5.4), whereas enlarged axillary lymph nodes were observed on DCE CT in 43 patients. Results for axillary node involvement were fairly well correlated (kappa = 0.55). Nineteen patients (38%) were found to be metastatic on PET/CT scan with a significant shorter progression-free survival than patients without distant lesions (p = 0.01). In the primary tumour, no statistically significant difference was observed between high and moderate tumour FDG uptake on survival, using an SUVmax cut-off of 5 (p = 0.7 and 0.9), or between high and low tumour enhancement on DCE CT (p0.8).FDG PET/CT imaging provided additional information concerning locoregional involvement to that provided by DCE CT on and allowed detection of distant metastases in the same whole-body procedure. Tumour FDG uptake or CT enhancement parameters were not correlated and were not found to have any prognostic value.

The purpose of this pilot study was to assess whether outcome in metastatic or recurrent breast cancer patients is related to metabolic response to endocrine therapy determined by (18)F-FDG PET/CT.The study group comprised 22 patients with breast cancer (age 58 ± 11 years, mean ± SD) who were scheduled to receive endocrine therapy. They were systematically assessed by PET/CT at baseline and after a mean of 10 ± 4 weeks for evaluation of response after induction. All patients demonstrated FDG-avid lesions on the baseline PET/CT scan. The metabolic response was assessed according to EORTC criteria and based on the mean difference in SUV(max) between the two PET/CT scans, and the patients were classified into four groups: complete or partial metabolic response, or stable or progressive metabolic disease (CMR, PMR, SMD and PMD, respectively). All patients were followed in our institution.Metastatic sites were localized in bone (n = 15), lymph nodes (n = 11), chest wall (n = 3), breast (n = 5), lung (n = 3), soft tissue (n = 1) and liver (n = 1). PMR was observed in 11 patients (50%), SMD in 5 (23%) and PMD in 6 (27%). The median progression-free survival (PFS) times were 20, 27 and 6 months in the PMR, SMD and PMD groups, respectively. PFS in the SMD group differed from that in the PMR and SMD groups (p0.0001).Metabolic response assessed by FDG PET/CT imaging in patients with metastatic breast cancer treated with endocrine therapy is predictive of the patients' PFS.

Hybrid systems associating the sharpness of anatomic images coming from computed tomography (CT) and radionuclide functional imaging (SPET or PET) are opening a new era in oncology. This multimodal imaging method is now routinely used for the diagnosis, extent, follow up, treatment response and detection of occult disease in different types of malignancies with a significant impact on the treatment strategy leading for a change for more than 68% of all investigated patients.

ObjectiveThe progression of medullary thyroid cancer is difficult to assess with imaging modalities; we studied the interest of calcitonin and carcinoembryonic antigen (CEA) doubling times and of Ki-67 labeling and mitotic index (MI).Patients and methodsFifty-five consecutive medullary thyroid carcinoma (MTC) patients with elevated calcitonin levels underwent repeated imaging studies in order to assess tumor burden and progression status. We looked for relationships between tumor burden and levels of calcitonin and CEA and between progression status according to the response evaluation criteria in solid tumors (RECIST) and calcitonin and CEA doubling times, and Ki-67 labeling and MI.ResultsThe calcitonin and CEA levels were correlated with tumor burden. Ten patients with calcitonin levels below 816 pg/ml had no imaged tumor foci. Among the 45 patients with imaged tumor foci, 19 had stable disease and 26 had progressive disease, according to the RECIST. The calcitonin and CEA doubling times were strongly related to disease progression, with very few overlaps: 94% of patients with doubling times shorter than 25 months had progressive disease and 86% of patients with doubling times longer than 24 months had stable disease. Ki-67 labeling and MI were not significantly associated with disease progression.ConclusionFor MTC patients, the doubling times of both calcitonin and CEA are efficient tools for assessing tumor progression.

Therapeutic options in patients with advanced-stage gastroenteropancreatic (GEP) neuroendocrine tumors are limited. We compared the efficacy of radionuclide therapy with 111In-pentetreotide and 131I-metaiodobenzylguanidine (MIBG) in 20 patients (group A) with the outcome of similar patients who could not be treated for nonmedical reasons (group B, n = 12). The intent was to treat all patients because of uncontrolled tumor disease (n = 21), contraindication to chemotherapy or surgery (n = 7), or uncontrolled and badly tolerated clinical symptoms (n = 4).Group A patients received 3 monthly administrations of 3.7-7.4 GBq of 131I-MIBG (n = 5) or 7 GBq of 111In-pentetreotide (n = 15), according to the best tracer uptake. Clinical evaluation, biologic tests, and conventional imaging were performed at 3, 6, 12, 18, and 24 mo. Therapy was considered beneficial if clinical status improved, laboratory tests for secreting tumors improved by20%, tumor progression was halted, the size of the most significant localization had decreased by25%, and the dosage of analgesic and cold somatostatin therapy could be lowered. Pejorative events were defined as side effects due to therapy, relapse in clinical symptoms, tumor progression, tumor laboratory marker increase, and death.The overall survival rate at 3 mo was significantly higher in group A (P = 0.05). Radionuclide therapy was beneficial in 14 patients (73% of group A), with only 1 significant side effect. The average time before relapse was 16.1 +/- 7.8 mo. The overall Kaplan-Meier survival rate and cumulative progression-free and cumulative event-free survival rates during the first 15 mo were significantly higher in patients receiving radionuclide therapy (P = 0.019, P = 0.024, and P = 0.019, respectively).Radionuclide therapy is feasible and safe and significantly defers the occurrence of fatal and nonfatal events in patients clinically uncontrolled by conventional therapy.

Objectifs Le pronostic des carcinomes peu differencies de la thyroide (CPDT) est heterogene quoique generalement pejoratif. Pourtant leur prise en charge therapeutique est identique a celle des autres cancers de souche folliculaire. L’objectif de cette etude etait d’evaluer la valeur de la reponse au traitement initial sur la survie et d’identifier des facteurs de mauvais pronostic dans le but de modifier la prise en charge et le suivi de ces patients. Patients et methodes Au total, 104 patients operes d’un CPDT entre le 01/01/2000 et le 31/12/2010 ont ete inclus dans cette etude et analyses de facon retrospective. Une relecture anatomo-pathologique a ete faite pour tous les cas. Resultats Le traitement initial a consiste en une thyroidectomie totale chez 101 patients (97,1 %). Le stade TNM etait majoritairement pT3 (55,8 %) et M1 dans 40,4 %. Une extension extra-thyroidienne (EET) a ete observee chez 40 patients (40 %). La chirurgie a ete suivie chez 99 patients (95,2 %) par une totalisation isotopique (TI). Le taux de thyroglobuline (Tg) a la TI etait ≥ 10 μg/l chez 47 patients (52,8 %) et ≥ 50 μg/l chez 40 patients (44,9 %). La remission clinique a l’issue de la TI et l’EET ont ete les seul facteurs pronostiques significatifs identifies en analyse multivariee pour la survie sans rechute. La survie globale n’etait influencee que par l’EET. Conclusion Les patients porteurs d’un CPDT, avec EET et/ou non en remission clinique apres la TI sont a risque important de rechute ou de poursuite evolutive et doivent beneficier d’un suivi rapproche.

6092 Background: Tyrosine kinase inhibitors (TKI) are currently used to treat patients with advanced iodine-refractory differentiated thyroid cancers (DTC) but none has been approved by the FDA or the EMA until now. Sometimes, patients are treated with off-label TKI when a clinical trial is not available or in second- and third-line therapy. Methods: We hereby report the efficacy of “off-label” sorafenib and sunitinib treatments as first-, second- and third-line therapy in metastatic DTC patients from the French TUTHYREF (TUmeurs THYroïdiennes REFractaires) network. Primary endpoints were progression free survival (PFS) and tumor response according to sequential TKI treatment. Secondary endpoint was organ-specific metastatic site analysis. Results: 45 patients with advanced iodine-refractory DTC treated with off-label TKI were included in this study (26 men, mean age: 62 years). 22 had papillary, 10 had follicular and 13 had poorly DTC. 24/45 patients were treated with two and 3/45 with three lines of TKIs. Sorafenib was the most frequently used (57%) followed by sunitinib (21.5%) and vandetanib (21.5%). Partial response (PR) rate was of 29% in the 21 patients who received first-line sorafenib therapy whereas PR was observed in 57% of the 7 first-line sunitinib patients. There was no PR with second- (n=24) and third-line (n=3) treatments. However, median progression free survival (PFS) was similar in second- as compared to first-line sorafenib or sunitinib treatment (6.7 vs. 7.6 months, HR 0.85 (95CI 0.45-1.61) p=0.6). Liver metastases were the most responsive to treatment (n=7; mean of -30%), followed by lung (n=57; mean of -19%) and lymph node (n=43; mean of -13%) metastases. Bone (n=14) and pleural (n=9) lesions were the most refractory to treatment (mean of -1% and -5%, respectively). Conclusions: Due to the small number of patients, we could not recommend a specific treatment sequence (sorafenib then sunitinib) over another (sunitinib then sorafenib). But TKI therapy appears to be beneficial in refractory DTC patients even in second- and third-line therapy, with similar PFS and stable disease as best response. Bone and pleural metastases were the most refractory and liver lesions the most responsive to treatment.