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ABSTRACT: BACKGROUND: Internal irradiation with iodine-131 (I)-labeled Lipiodol is one of the currently available forms of palliative therapy for patients with advanced hepatocellular carcinoma (HCC). Despite a cumulative experience of more than 10 years with this treatment, only a few studies have reported on its efficacy and safety. OBJECTIVE: The aim of this study was to retrospectively evaluate the efficacy of intra-arterial I-labeled Lipiodol injection for treatment against advanced HCC. MATERIALS AND METHODS: Fifty patients (47 men and three women; mean age 64 years) given an intra-arterial injection of I-Lipiodol (5 ml of 2.2 GBq Lipiodol labeled with I; number of mean sessions per patient, 1.3; range 1-4) were retrospectively compared with 36 patients (31 men and five women; mean age 64 years) who were given only medical support. Portal vein thrombosis was present in 86 and 100% of patients, respectively. Efficacy was determined on the basis of overall survival as the endpoint using the Kaplan-Meier method. Tumor response was evaluated with computed tomography according to Response Evaluation Criteria In Solid Tumors (RECIST 1.1) and European Association for the Study of the Liver (EASL) criteria. RESULTS: For patients treated with I-Lipiodol, median survival was 32 weeks, compared with 8 weeks for the untreated group (P=0.007). Survival at 6 months and at 1 and 2 years was 65, 35, and 22%, respectively, for patients treated with I-Lipiodol compared with 28, 8, and 0% for the untreated group. At 1 month, more than 80% of patients were responders (complete response, partial response, and stable disease) on the basis of the RECIST and EASL criteria, and at 6 months 39% were responders. No radiotoxic effect was observed, especially with respect to interstitial pneumonia. No significant difference was observed between survival and α-fetoprotein levels, Barcelona Clinic Liver Cancer clinical score, and portal vein thrombosis. CONCLUSION: Intra-arterial injection of I-Lipiodol is safe and provides significant survival benefit in terms of overall survival for patients with advanced HCC.
Nuclear Medicine Communications 04/2013; · 1.40 Impact Factor
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ABSTRACT: BACKGROUND: Despite the early theoretical prediction of the 0+-0+ transition of 90Zr, 90Y-PET underwent only recently a growing interest for the development of imaging radioembolization of liver tumors. The aim of this work was to determine the minimum detectable activity (MDA) of 90Y by PET imaging and the impact of time-of-flight (TOF) reconstruction on detectability and quantitative accuracy according to the lesion size. METHODS: The study was conducted using a Siemens Biograph(R) mCT with a 22 cm large axial field of view. An IEC torso-shaped phantom containing five coplanar spheres was uniformly filled to achieve sphere-to-background ratios of 40:1. The phantom was imaged nine times in 14 days over 30 min. Sinograms were reconstructed with and without TOF information. A contrast-to-noise ratio (CNR) index was calculated using the Rose criterion, taking partial volume effects into account. The impact of reconstruction parameters on quantification accuracy, detectability, and spatial localization of the signal was investigated. Finally, six patients with hepatocellular carcinoma and four patients included in different 90Y-based radioimmunotherapy protocols were enrolled for the evaluation of the imaging parameters in a clinical situation. RESULTS: The highest CNR was achieved with one iteration for both TOF and non-TOF reconstructions. The MDA, however, was found to be lower with TOF than with non-TOF reconstruction. There was no gain by adding TOF information in terms of CNR for concentrations higher than 2 to 3 MBq mL-1, except for infra-centimetric lesions. Recovered activity was highly underestimated when a single iteration or non-TOF reconstruction was used (10 % to 150 % less depending on the lesion size). The MDA was estimated at 1 MBq mL-1 for a TOF reconstruction and infra-centimetric lesions. Images from patients treated with microspheres were clinically relevant, unlike those of patients who received systemic injections of 90Y. CONCLUSIONS: Only one iteration and TOF were necessary to achieve an MDA around 1 MBq mL-1 and the most accurate localization of lesions. For precise quantification, at least three iterations gave the best performance, using TOF reconstruction and keeping an MDA of roughly 1 MBq mL-1. One and three iterations were mandatory to prevent false positive results for quantitative analysis of clinical data.Trial registration: IDRCB 2011-A00043-38 P101103.
EJNMMI research. 02/2013; 3(1):11.
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Pierre-Yves Salaun,
Loïc Campion,
Claire Bournaud,
Alain Faivre-Chauvet,
Jean-Philippe Vuillez,
David Taieb,
Catherine Ansquer,
Caroline Rousseau,
Françoise Borson-Chazot,
Stéphane Bardet,
Aurore Oudoux,
Bertrand Cariou,
Eric Mirallié,
Chien-Hsing Chang,
Robert M Sharkey,
David M Goldenberg,
Jean-François Chatal,
Jacques Barbet, Françoise Kraeber-Bodéré
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ABSTRACT: The prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival based on such prognostic factors as serum calcitonin and carcinoembryonic antigen (CEA) doubling times (DTs). This prospective phase II multicenter trial evaluated the efficacy and safety of anti-CEA pretargeted radioimmunotherapy (pRAIT) in rapidly progressing metastatic MTC patients and also how serum biomarker DTs correlate with clinical outcome.
From June 2004 to January 2008, 42 patients were treated with anti-CEA × anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody (hMN-14 × m734) (40 mg/m(2)), followed by (131)I-di-DTPA-indium bivalent hapten (1.8 GBq/m(2)) 4-6 d later.
The disease control rate (durable stabilization plus objective response) was 76.2%. Grade 3-4 hematologic toxicity was observed in 54.7% of patients and myelodysplastic syndrome in 2, including 1 heavily treated previously. After pRAIT, 21 of 37 assessed patients (56.7%) showed a significant impact on DT (≥100% increase of pre-pRAIT calcitonin or CEA DT or prolonged decrease of the biomarker concentration after pRAIT). Pre-pRAIT DT and post-pRAIT DT were significant independent predictors for overall survival (OS) from pRAIT (pre-pRAIT: hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.86; P = 0.016; and post-pRAIT: HR, 5.32; 95% CI, 1.63-17.36; P = 0.006) and OS from diagnosis (pre-pRAIT: HR, 0.21; 95% CI, 0.08-0.51; P = 0.001; and post-pRAIT: HR, 6.16; 95% CI, 1.81-20.98; P = 0.004).
pRAIT showed antitumor activity, with manageable hematologic toxicity in progressive MTC. Increased biomarker DT after treatment correlated with increased OS.
Journal of Nuclear Medicine 06/2012; 53(8):1185-92. · 6.38 Impact Factor
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Journal of Clinical Oncology 05/2012; 30(17):2165; author reply 2166-7. · 18.37 Impact Factor
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ABSTRACT: Prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival, based on prognostic factors, such as serum calcitonin doubling time (Ct DT). Pretargeted radioimmunotherapy (pRAIT) is a novel targeted radionuclide therapy, using a bispecific monoclonal antibody (BsMAb) and a radiolabeled bivalent hapten, designed to improve the therapeutic index and to deliver increased tumor-absorbed doses to relatively radioresistant solid tumors. Pretargeting has demonstrated a more favorable therapeutic index and clinical efficacy than directly labeled anti-carcinoembryonic antigen (CEA) MAb in preclinical MTC models. Moreover, two phase I/II clinical trials assessing anti-CEA × anti-DTPA-indium BsMAb (murine F6x734 and chimeric hMN14x734) with (131)I-di-DTPA-indium showed encouraging therapeutic results in progressive, metastatic, MTC patients, with an improved survival in intermediate- and high-risk (pre-pRAIT Ct DT, <2 years) patients, as compared to contemporaneous untreated patients (median overall survival, 110 months vs 61 months; P < 0.030). pRAIT efficacy has been recently confirmed in a prospective multicenter phase II study assessing hMN14x734 and (131)I-di-DTPA-indium in rapidly progressive MTC patients. New pRAIT compounds are now available with fully humanized, recombinant, trivalent BsMAb (anti-CEA TF2) and histamine-succinyl-glutamine (HSG) peptides. The HSG peptide allows easy and stable labeling with different radiometals, such as (177)Lu or (90)Y beta-emitters having favorable physical features for pRAIT or (68)Ga and (18)F positron-emitters, allowing the development of a highly sensitive and specific immuno-positron emission tomography method in MTC or other CEA-positive tumors.
Tumor Biology 03/2012; 33(3):601-6. · 1.94 Impact Factor
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Caroline Rousseau,
Ludovic Ferrer,
Stéphane Supiot,
Manuel Bardiès,
François Davodeau,
Alain Faivre-Chauvet,
Pierre Baumgartner,
John Wijdenes,
Marie Lacombe,
Jacques Barbet,
Thierry Guillaume,
Philippe Moreau,
Jean Luc Harousseau, Françoise Kraeber-Bodéré,
Michel Cherel
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ABSTRACT: Syndecan-1 (CD138), a heparan sulfate proteoglycan, is constantly expressed on tumor cells in multiple myeloma (MM). This surface antigen is an attractive candidate for targeted therapy, especially radioimmunotherapy (RAIT). We report preliminary biodistribution and dosimetry results obtained in refractory MM patients in a phase I/II RAIT study using iodine-131-labeled anti-CD138 (B-B4) monoclonal antibody (mAb). Four patients with progressive disease were enrolled after three lines of therapy. They received 370 MBq (20 mg/m(2)) of (131)I-B-B4 for the dosimetry study. Each patient underwent a whole body (WB) CT and four WB emission scans at days D0, D1, and D3-4. Images were corrected for attenuation and scatter to assess doses absorbed by organs and bone marrow (BM). Blood and urine samples were additionally collected. Dosimetry was conducted using the MIRD method. Images obtained 1 h after (131)I-B-B4 injection showed high BM and liver uptake without kidney uptake. The BM uptake confirmed BM involvement as detected by pre-inclusion FDG PET/CT. Absorbed doses were calculated at 2.03 ± 0.3 mGy/MBq for the liver, 1.10 ± 0.9 mGy/MBq for the kidneys, and 0.52 ± 0.20 mGy/MBq for the BM. Grade III thrombocytopenia was documented in two cases (highest BM-absorbed doses), and no grade IV hematological toxicity was observed. Therefore, autologous stem cells were not infused. One patient out of four experienced partial response, with 60% reduction of M-spike on serum electrophoresis, and total relief of pain, lasting for 1 year. This patient was able to go back to work. In this proof of concept study based on dosimetry, we show that MM RAIT is feasible using the anti-CD138 antibody. It would be of great interest to perform a RAIT phase I/II trial with a humanized anti-CD138 mAb with increased doses and systematic autologous stem cell infusions to overcome hematological toxicity and achieve efficacy.
Tumor Biology 03/2012; 33(3):679-88. · 1.94 Impact Factor
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ABSTRACT: Radiolabeled antibodies were studied first for tumor detection by single-photon imaging, but FDG PET stopped these developments. In the meantime, radiolabeled antibodies were shown to be effective in the treatment of lymphoma. Radiolabeling techniques are well established and radiolabeled antibodies are a clinical and commercial reality that deserves further studies to advance their application in earlier phase of the diseases and to test combination and adjuvant therapies including radiolabeled antibodies in hematological diseases. In solid tumors, more resistant to radiations and less accessible to large molecules such as antibodies, clinical efficacy remains limited. However, radiolabeled antibodies used in minimal or small-size metastatic disease have shown promising clinical efficacy. In the adjuvant setting, ongoing clinical trials show impressive increase in survival in otherwise unmanageable tumors. New technologies are being developed over the years: recombinant antibodies and pretargeting approaches have shown potential in increasing the therapeutic index of radiolabeled antibodies. In several cases, clinical trials have confirmed preclinical studies. Finally, new radionuclides, such as lutetium-177, with better physical properties will further improve the safety of radioimmunotherapy. Alpha particle and Auger electron emitters offer the theoretical possibility to kill isolated tumor cells and microscopic clusters of tumor cells, opening the perspective of killing the last tumor cell, which is the ultimate challenge in cancer therapy. Preliminary preclinical and preliminary clinical results confirm the feasibility of this approach.
Methods in molecular biology (Clifton, N.J.) 01/2012; 907:681-97.
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Caroline Rousseau,
Thierry Rousseau,
Boumédiène Bridji,
Amandine Pallardy,
Jacques Lacoste,
Loïc Campion,
Aude Testard,
Geneviève Aillet,
Ayat Mouaden,
Chantal Curtet, Françoise Kraeber-Bodéré
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ABSTRACT: Lymph node metastasis is an important prognostic factor in prostate cancer (PC). The aim of this prospective study was to evaluate the accuracy of sentinel lymph node (SLN) biopsy by laparoscopy in staging locoregional patients with clinically localized PC.
A transrectal ultrasound-guided injection of 0.3 ml/100 MBq (99m)Tc-sulphur rhenium colloid in each prostatic lobe was performed the day before surgery. Detection was performed intraoperatively with a laparoscopic probe (Gamma Sup CLERAD) followed by extensive resection. SLN counts were performed in vivo and confirmed ex vivo. Histological analysis was performed by haematoxylin-phloxine-saffron staining, followed by immunohistochemistry (IHC) if the SLN was free of metastasis.
The study included 93 patients with PC at intermediate or high risk of lymph node metastases. The intraoperative detection rate was 93.5% (87/93). Nineteen patients had lymph node metastases, nine only in SLN. The false-negative rate was 10.5% (2/19). The internal iliac region was the primary metastatic site (43.3%). Metastatic sentinel nodes in the common iliac region beyond the ureteral junction were present in 13.3%. Limited or standard lymph node resection would have ignored 73.2 and 56.6% of lymph node metastases, respectively.
Laparoscopy is suitable for broad identification of SLN metastasis, and targeted resection of these lymph nodes significantly limits the risk of extended surgical resection whilst maintaining the accuracy of the information.
European Journal of Nuclear Medicine 11/2011; 39(2):291-9. · 4.53 Impact Factor
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ABSTRACT: Early detection is an essential prognostic factor in colorectal cancer (CRC) recurrence. Our aim was to evaluate diagnostic performances of (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET)/computed tomography (CT) as compared with CT in the detection of CRC recurrence.
Data of patients with suspected CRC recurrence and in whom both FDG-PET/CT and CT were performed were analyzed. All detected lesions were characterized according to their number, size, and localization. Positive histological or radiological follow-up was considered as the 'gold standard'. Diagnostic performances of FDG-PET/CT and CT were calculated by lesion, globally and with respect to the site of recurrence.
One hundred and seventy-six true-positive lesions were identified in 71 patients. CT scan was positive in 58 (82%) patients and FDG-PET/CT in 70 (98%) patients. In per lesion analysis, the global accuracy of FDG-PET/CT in detection of lesions was of 88% (sensitivity = 95%, specificity = 54%), which was higher than that of CT (53%, sensitivity = 55%, specificity = 43%), particularly in case of lymph nodes metastases (100 vs. 35%) and locoregional lesions (100 vs. 39%) (P<0.0001). FDG-PET/CT modified the clinical management in 31 patients.
FDG-PET/CT is more sensitive than CT for diagnosis of CRC recurrence and can modify the management in 40% of patients.
European journal of gastroenterology & hepatology 03/2011; 23(3):275-81. · 1.66 Impact Factor
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ABSTRACT: Regional axillary lymph node status has remained the single most independent variable to predict prognosis both in terms of disease recurrence and survival. This study aimed to prospectively assess sequential [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) findings as early predictors of axillary lymph node response to neoadjuvant chemotherapy in stage II and III breast cancer patients.
Images were acquired with a PET/CT scanner in 52 patients after administration of FDG (5 MBq/kg) at baseline and after the first, second, third and sixth course of chemotherapy before surgery. Clinical examination and ultrasound (US) were used to assess the size of axillary nodes. Decrease in the standardized uptake value (SUV) with PET corrected or not for partial volume effects was compared to the pathological response.
The sensitivity, specificity and accuracy of axillary node staging was higher with PET (75, 87 and 80%) than with US (50, 83 and 65%), and even more so when PET images were corrected for partial volume effects (86, 83 and 84%). While FDG uptake did not vary much in non-responders, as confirmed by histopathological analysis, it markedly decreased to baseline levels in responders (p < 10(-5)). Fifty per cent of baseline SUV was considered the best cutoff value to distinguish responders from non-responders. The sensitivity, specificity, negative predictive value and accuracy of FDG PET after one course of chemotherapy were, respectively, 96, 75, 95 and 84%.
The pathological status of regional axillary lymph nodes in stage II and III breast cancer patients could be accurately predicted after one course of neoadjuvant chemotherapy based on FDG PET images.
European Journal of Nuclear Medicine 02/2011; 38(6):1029-36. · 4.53 Impact Factor
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Caroline Rousseau,
Anne Lise Ruellan,
Karine Bernardeau, Françoise Kraeber-Bodéré,
Sebastien Gouard,
Delphine Loussouarn,
Catherine Saï-Maurel,
Alain Faivre-Chauvet,
John Wijdenes,
Jacques Barbet,
Joëlle Gaschet,
Michel Chérel,
François Davodeau
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ABSTRACT: Overexpression of syndecan-1 (CD138) in breast carcinoma correlates with a poor prognosis and an aggressive phenotype. The objective of this study was to evaluate the potential of targeting CD138 by immuno-PET imaging and radioimmunotherapy (RIT) using the antihuman syndecan-1 B-B4 mAb radiolabeled with either 124I or 131I in nude mice engrafted with the triple-negative MDA-MB-468 breast cancer cell line.
The immunoreactivity of 125I-B-B4 (80%) was determined, and the affinity of 125I-B-B4 and the expression of CD138 on MDA-MB-468 was measured in vitro by Scatchard analysis. CD138 expression on established tumors was confirmed by immunohistochemistry. A biodistribution study was performed in mice with subcutaneous MDA-MB-468 and 125I-B-B4 at 4, 24, 48, 72, and 96 h after injection and compared with an isotype-matched control. Tumor uptake of B-B4 was evaluated in vivo by immuno-PET imaging using the 124I-B-B4 mAb. The maximum tolerated dose (MTD) was determined from mice treated with 131I-B-B4 and the RIT efficacy evaluated.
125I-B-B4 affinity was in the nanomolar range (Kd = 4.39 ± 1.10 nM). CD138 expression on MDA-MB-468 cells was quite low (Bmax = 1.19 × 104 ± 9.27 × 102 epitopes/cell) but all expressed CD138 in vivo as determined by immunohistochemistry. The tumor uptake of 125I-B-B4 peaked at 14% injected dose (ID) per gram at 24 h and was higher than that of the isotype-matched control mAb (5% ID per gram at 24 h). Immuno-PET performed with 124I-B-B4 on tumor-bearing mice confirmed the specificity of B-B4 uptake and its retention within the tumor. The MTD was reached at 22.2 MBq. All mice treated with RIT (n = 8) as a single treatment at the MTD experienced a partial (n = 3) or complete (n = 5) response, with three of them remaining tumor-free 95 days after treatment.
These results demonstrate that RIT with 131I-B-B4 could be considered for the treatment of metastatic triple-negative breast cancer that cannot benefit from hormone therapy or anti-Her2/neu immunotherapy. Immuno-PET for visualizing CD138-expressing tumors with 124I-B-B4 reinforces the interest of this mAb for diagnosis and quantitative imaging.
EJNMMI research. 01/2011; 1(1):20.
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Franck Morschhauser, Françoise Kraeber-Bodéré,
William A Wegener,
Jean-Luc Harousseau,
Marie-Odile Petillon,
Damien Huglo,
Lorenz H Trümper,
Johannes Meller,
Michael Pfreundschuh,
Carl-Martin Kirsch,
Ralph Naumann,
Joachim Kropp,
Heather Horne,
Nick Teoh,
Steven Le Gouill,
Caroline Bodet-Milin,
Jean-Francois Chatal,
David M Goldenberg
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ABSTRACT: Fractionated radioimmunotherapy targeting CD22 may substantially improve responses and outcome in non-Hodgkin's lymphoma (NHL).
A multicenter trial evaluated two or three weekly infusions of yttrium-90 ((90)Y) epratuzumab tetraxetan (humanized anti-CD22 antibody) in 64 patients with relapsed/refractory NHL, including 17 patients who underwent prior autologous stem-cell transplantation (ASCT). Objective (OR) and complete responses (CR/complete response unconfirmed [CRu]), as well as progression-free survival (PFS), were determined.
At the maximum total (90)Y dose of 45 mCi/m(2) (1,665 MBq/m(2)), grade 3 to 4 hematologic toxicities were reversible to grade 1 in patients with less than 25% bone marrow involvement. The overall OR rate and median PFS for all 61 evaluable patients was 62% (CR/CRu, 48%) and 9.5 months, respectively. Patients without prior ASCT obtained high OR rates of 71% (CR/CRu, 55%) across all NHL subtypes and (90)Y doses, even in poor-risk categories (refractory to last anti-CD20-containing regimen, 73% [CR/CRu, 60%]; bulky disease: 71% [CR/CRu, 43%]). Patients with prior ASCT received lower doses, but achieved an OR rate of 41% (CR/CRu, 29%). For patients with follicular lymphoma (FL), OR rates and median PFS increased with total (90)Y-dose, reaching 100% (CR/CRu, 92%) and 24.6 months, respectively, at the highest dose levels (> 30 mCi/m(2) total (90)Y-dose [1,110 MBq/m(2)]). Further, patients with FL refractory to prior anti-CD20-containing regimens achieved 90% (nine of 10 patients) OR and CR/CRu rates and a median PFS of 21.5 months.
Fractionated anti-CD22 radioimmunotherapy provides high total doses of (90)Y, yielding high rates of durable CR/CRus in relapsed/refractory NHL, resulting in 20 mCi/m(2) x 2 weeks as the recommended dose for future studies.
Journal of Clinical Oncology 08/2010; 28(23):3709-16. · 18.37 Impact Factor
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Catherine Ansquer,
Sonia Scigliano,
Eric Mirallié,
David Taïeb,
Laurent Brunaud,
Fredéric Sebag,
Christophe Leux,
Delphine Drui,
Benoît Dupas,
Karine Renaudin, Françoise Kraeber-Bodéré
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ABSTRACT: This prospective multicentre study assesses the usefulness of FDG PET/CT in characterizing and making the therapeutic decision concerning adrenal tumours that are suspicious or indeterminate in nature after conventional examinations (CE).
Seventy-eight patients (37 men, 41 women, 81 adrenal lesions) underwent FDG PET/CT after CE including CT scan, biological tests and optionally (131)I-metaiodobenzylguanidine (MIBG) and/or (131)I-norcholesterol scans. FDG adrenal uptake exceeding that of the liver was considered positive. PET results were not decisive. Surgery was discussed when at least one of the following criteria was found during CE: size >3 cm, spontaneous attenuation value >10 HU, heterogeneous aspect, abnormal MIBG or norcholesterol scan or hormonal hypersecretion.
Following the gold standard (histology analysis or >or=9 months follow-up), 49 lesions potentially qualified for surgery (malignant = 27, benign secreting = 22) and 32 benign non-secreting lesions did not. PET was negative in 97% of non-surgical lesions and positive in 73% of potentially surgical ones which included all the malignant lesions, except 3 renal cell metastases, and 12 of 22 benign secreting lesions. The negative predictive value for malignancy was 93% (41/44) and positive predictive value for detecting surgical lesions was 97% (36/37). A high FDG uptake (maximum standardized uptake value >or= 10) was highly predictive of malignancy.
Adrenal FDG uptake is a good indicator of malignancy and/or of secreting lesions and should lead one to discuss surgery. If there is no prior history of poorly FDG-avid cancer, the absence of FDG uptake should avoid unnecessary removal of benign adrenal lesions.
European Journal of Nuclear Medicine 08/2010; 37(9):1669-78. · 4.53 Impact Factor
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Françoise Kraeber-Bodéré,
Caroline Bodet-Milin,
Colin Niaudet,
Catherine Saï-Maurel,
Anne Moreau,
Alain Faivre-Chauvet,
Patrick Thomare,
Gerard Deleris,
Karine Estieu-Gionnet,
Andréas Bikfalvi,
Jacques Barbet,
François Paris
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ABSTRACT: A significant antitumor effect was previously observed with radioimmunotherapy using anti-carcinoembryonic antigen (131)I-F6 monoclonal antibody in medullary thyroid cancer-bearing nude mice. Nevertheless, no complete response was observed. As seen with chemotherapy, drugs targeting the tumor microenvironment might improve radioimmunotherapy efficacy. This study evaluated the toxicity and efficacy of combining radioimmunotherapy with thalidomide or a cyclopeptidic vascular endothelial growth inhibitor (CBOP11) in mice grafted with the TT human medullary thyroid cancer cell line.
Six to 10 nude mice treated with 92.5 MBq of (131)I-F6 in association with 200 mg/kg/d of oral thalidomide during 20 d by force-feeding or 0.45 mg/kg/d of CBOP11 during 25 d using subcutaneous minipumps were compared with control mice receiving either treatment or naked F6 or nonspecific (131)I-734. Combined therapies included (131)I-F6 at day 0 followed by thalidomide between days 20 and 40, thalidomide between days 0 and 20 followed by (131)I-F6 at day 25, (131)I-F6 at day 0 and CBOP11 between days 0 and 25, CBOP11 between days 0 and 25 followed by (131)I-F6 at day 25, and (131)I-F6 at day 0 followed by CBOP11 between days 20 and 45. Animal weight, hematologic toxicity, tumor volume, and serum calcitonin were monitored for the following 3 mo. Improvement of (125)I-F6 tumor biodistribution by antiangiogenic drug was studied after pretreatment by thalidomide. Follow-up of the tumor after combined antiangiogenic and radioimmunotherapy therapies was performed by histology studies.
Combined associations, as compared with radioimmunotherapy alone, increased leukopenia but not thrombocytopenia. Tumor volume-quadrupling time (TVQT) was 22.8 +/- 3.3 d in the control group, 29.9 +/- 3.6 d in the group treated with thalidomide, 34.6 +/- 4.4 d in the group treated with CBOP11, and 51.0 +/- 2.8 d after radioimmunotherapy alone. As compared with radioimmunotherapy, TVQT was significantly longer (P < 0.01) after thalidomide followed by radioimmunotherapy (69.83 +/- 3.9), CBOP11 followed by radioimmunotherapy (71.3 +/- 6.1), and CBOP11-radioimmunotherapy in concomitance (64.2 +/- 6.1). Nevertheless, TVQT was not increased after radioimmunotherapy followed by thalidomide (48.8 +/- 4) and radioimmunotherapy followed by CBOP11 (56.8 +/- 4.8). Surprisingly, pretreatment by CBOP11 or thalidomide sensitized larger tumors (>300 mm(3)) to radioimmunotherapy. Change in calcitonin levels confirmed morphologic tumor response. Tumor uptake 24 h after injection of (125)I-F6 was 4.5 +/- 0.6 percentage injected dose per gram (%ID/g) without pretreatment and 8.7 +/- 1.3 %ID/g with pretreatment by thalidomide. An increase of the antitumor effect observed using the antiangiogenic drug combined with radioimmunotherapy was correlated with a decrease of blood vessels shown by von Willebrand immunostaining.
Pretreatment with antiangiogenic therapies improved radioimmunotherapy efficacy, with acceptable toxicity. Future investigations will be performed to understand how antiangiogenic agents sensitize large tumors to radioimmunotherapy.
Journal of Nuclear Medicine 04/2010; 51(4):624-31. · 6.38 Impact Factor
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Amandine Pallardy,
Caroline Bodet-Milin,
Aurore Oudoux,
Loïc Campion,
Emmanuelle Bourbouloux,
Christine Sagan,
Catherine Ansquer,
Aude Testard,
Isabelle Resche,
Boumédiène Bridji, Françoise Kraeber-Bodéré,
Caroline Rousseau
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ABSTRACT: The aim of this retrospective study was to evaluate the contribution of (18)F-FDG PET to the clinical management and survival outcome of patients suspected of recurrent cervical carcinoma and in line with the hypothesis that early diagnosis of recurrent cervical cancer may improve overall survival.
A total of 40 patients underwent conventional imaging (CI) and FDG PET/CT for suspected cervical cancer. Clinical management decisions were recorded with CI and additional PET/CT. Discordances and concordances between CI and PET/CT results were compared to the final diagnosis as based on histopathology analysis or follow-up considered as the gold standard.
The final diagnosis was established pathologically (n = 25) or by median clinical follow-up for 48 months after the PET (n = 15). The PET/CT was positive in 76% (20/26) of patients compared to 19% (6/26) with CI. Globally PET/CT modified the treatment plan in 55% (22/40) of patients and in 75% (18/24) when the CI was negative prior to PET/CT. These changes led to the use of previously unplanned therapeutic procedures in 37.5% (15/40). When FDG PET was positive for recurrence (> 3 foci), the median overall survival was 12 months (2-70) compared to patients with PET findings with < or = 1 focus for which the median survival was not attained (p = 0.007). A multivariate analysis of prognostic factors demonstrated that abnormal FDG uptake (> 3 foci) was the most significant factor (p < 0.03) for death from cervical cancer.
FDG PET is a valuable tool in the case of suspected recurrence of cervical cancer on account of its impact on treatment planning and especially in predicting patient outcome.
European Journal of Nuclear Medicine 03/2010; 37(7):1270-8. · 4.53 Impact Factor
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ABSTRACT: Maximum injected activity in radioimmunotherapy (RIT) is limited by bone marrow toxicity. Many dosimetric approaches have been proposed, leading to high variability in the results and elusive absorbed dose-effect relations. This study presents the results of red marrow (RM) absorbed dose estimates performed with 3 methods.
Five patients received 2 co-infusions of (90)Y-labeled (370 MBq/m2) and (111)In- labeled (120 MBq) epratuzumab (1.5 mg/kg) 1 week apart. RM-absorbed dose was estimated by 3 methodologies. The first approach (M1) used L(2)-L(4) lumbar vertebrae imaging. M2 and M3 methods used different red marrow to blood ratios (RMBLR) to assess RM-absorbed dose. RMBLR was set to a fixed value of 0.36 in M2 or assessed according to each patient's hematocrit in M3.
Median RM-absorbed doses were 4.1 (2.9-8.4), 2.3 (2.0-2.7), and 2.3 (1.6-2.5) mGy/MBq for M1, M2, and M3, respectively. No trend could be found between total RM-absorbed dose and toxicity for M2 and M3. Conversely, M1 seemed to provide the best absorbed dose-effect relation. The 4 patients with the highest RM-absorbed doses exhibited grade 4 toxicity. The fifth patient, with the lowest RB absorbed dose, exhibited only a mild (grade 2) toxicity.
Image-based methodology (M1) seems to better predict hematological toxicity as compared with blood-based methods. Only this method provides for bone marrow involvement.
Cancer 02/2010; 116(4 Suppl):1093-100. · 4.77 Impact Factor
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ABSTRACT: Significant antitumor effects were previously observed with radioimmunotherapy (RIT) using an anti-carcinoembryonic antigen (CEA) monoclonal antibody (F6) labeled with iodine-131 in medullary thyroid cancer (MTC)-bearing nude mice. Nevertheless, no complete response was achieved. Because angiogenesis is critical for tumor growth, bevacizumab is used to treat solid tumor in clinical practice. The present pilot study evaluated toxicity and efficacy of RIT combined with bevacizumab in mice subcutaneously grafted with TT MTC cells.
Groups of 4-6 nude mice were treated with 5 microg/g bevacizumab twice weekly during 4 weeks and/or 100 MBq of (131)I-F6. For combined therapy, bevacizumab was given at Day 0 followed by (131)I-F6 at Day 30. The control group received no treatment. Animal weight, hematological toxicity, tumor volume, and serum calcitonin were monitored for 2 or 4 months.
Bevacizumab alone induced no cytopenia and no significant weight loss. A weight loss of 12 +/- 1% and 15 +/- 2% was observed in mice treated by RIT alone or bevacizumab + RIT, respectively. RIT alone and combined treatment induced leukopenia and anemia. RIT alone and RIT plus bevacizumab induced tumor responses with minimum relative tumor volume of 0.38 +/- 0.24 and 0.15 +/- 0.07%, respectively, and time to progression of 35 +/- 5 and 56 +/- 11 days, respectively.
Pretreatment with bevacizumab improved RIT efficacy, with similar toxicity as compared as RIT alone.
Cancer 02/2010; 116(4 Suppl):1053-8. · 4.77 Impact Factor
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ABSTRACT: Medullary thyroid cancer (MTC) patients with localized residual disease and/or distant metastases may survive for several years or rapidly progress and die of their disease. Thus, highly reliable prognostic factors are needed for an early distinction between high-risk patients who need to be treated and low-risk patients who warrant a watch-and-wait approach. Calcitonin doubling time is an independent predictor of survival, with a high predictive value in a population of patients who have not normalized their calcitonin, even after repeated surgery. Several imaging methods should be proposed for patients with abnormal residual calcitonin levels persisting after complete surgery: ultrasonography and computed tomography (CT) for neck exploration, and CT for chest, abdomen, and pelvis. Magnetic resonance imaging (MRI) appears to have an advantage over CT for the detection of liver metastases from endocrine tumors. Moreover, MRI appears to be a sensitive imaging technique for detecting the spread of MTC to bone/bone marrow. 2-Fluoro-2-deoxy-D-glucose positron emission tomography/CT could be used for staging patients with progressive MTC, with possible prognostication by standard uptake value quantification. For systemic treatment of patients with rapidly progressing metastatic MTC, chemotherapy is not considered a valid therapeutic option. It is too early to evaluate the potential effectiveness of multikinase inhibitors, although interesting results of phase 2 studies have shown a transient stabilization in 30% to 50% of patients. Pretargeted radioimmunotherapy has been the only innovative treatment modality convincingly showing some survival benefit when compared with a historical untreated control group.
Cancer 02/2010; 116(4 Suppl):1118-25. · 4.77 Impact Factor
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ABSTRACT: The first treatment ever by radio-immunotherapy (RIT) was performed by William H. Beierwaltes in 1951 and was a success. Fifty years later, the main question is to find ways of extending the success of radiolabelled anti-CD20 antibodies in indolent non-Hodgkin's lymphoma to other forms of cancer. Solid tumours are much more radioresistant than lymphomas, but they respond to RIT if the lesions are small. Clinical situations of residual or minimal disease are thus the most likely to benefit from RIT in the adjuvant or consolidation settings. For disseminated disease, like leukemias or myelomas, the problem is different: beta- particles emitted by the radioactive atoms classically used for cancer treatment (iodine-131 or yttrium-90) disperse their energy in large volumes (ranges 1 mm to 1 cm) and are not very effective against isolated cells. Advances in RIT progress in two directions. One is the development of pretargeting strategies in which the antibody is not labelled but used to provide binding sites to small molecular weight radioactivity vectors (biotin, haptens). These techniques have been shown to increase tumour to non-target uptake ratios and anti-tumour efficacy has been demonstrated in the clinic. The other approach is the use of radionuclides adapted to the various clinical situations. Lutetium-177 or copper-67, because of the lower energy of their emission, their relatively long half-life and good gamma emission, may significantly improve RIT efficacy and acceptability. Beyond that, radionuclides emitting particles such as alpha particles or Auger electrons, much more efficient to kill isolated tumour cells, are being tested for RIT in the clinic. Finally, RIT should be integrated with other cancer treatment approaches in multimodality protocols. Thus RIT, now a mature technology, should enter a phase of well designed and focused clinical developments that may be expected to afford significant therapeutic advances.
Medecine sciences: M/S 12/2009; 25(12):1039-45. · 0.64 Impact Factor
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ABSTRACT: (18)F-FDG PET has been successfully evaluated in the management of Hodgkin's lymphoma (HL) and the most recent international guidelines recommended (18)F-FDG PET for initial staging and final therapeutic assessment. However, (18)F-FDG PET diffuse bone marrow uptake (BMU) and splenic uptake (SU) are frequently observed at the initial imaging and remain difficult to analyse. The aim of this retrospective study was to evaluate the significance of (18)F-FDG diffuse BMU and SU in initial staging of HL.
A total of 106 patients (median age: 31 years, range: 9-81, 51 female, 55 male) underwent (18)F-FDG PET/CT for initial staging of HL. BMU level was assessed visually according to liver uptake (1 = below liver uptake, 2 = corresponding to liver uptake, 3 = above liver uptake) and semi-quantitatively using the maximum standardized uptake value (SUV(max)) measured in the sacral area. SU was assessed visually according to liver uptake (1 = below liver uptake, 2 = corresponding to liver uptake, 3 = above liver uptake). These data were compared with the patient's characteristics including sex, age, Ann Arbor staging, bulky disease (tumour burden > 10 cm), presence of B symptoms, bone foci on PET (n = 106), bone marrow involvement (BMI) on biopsy (n = 75), leukocyte count (n = 74), lactic dehydrogenase (LDH) (n = 87), C-reactive protein (CRP) (n = 83) and fibrinogen (n = 60). Univariate and multivariate analyses were performed.
Multivariate analysis found an independent correlation between BMU visual grading and CRP level (p = 0.007). For semi-quantitative BMU evaluation, multivariate analysis found an independent correlation between sacral SUVs and CRP level (p = 0.032) and Ann Arbor stage (p = 0.005). No BMI was found in patients who presented with SUV(max) below 3.4. For splenic evaluation, multivariate analysis found an independent correlation between SU and splenic foci (p = 0.034). No statistical link was found between SU and inflammatory markers.
Our study demonstrates that diffuse BMU at initial staging of HL could be due to bone marrow involvement but more likely to bone marrow inflammatory change and that diffuse SU in contrast is probably more associated with disease involvement than with inflammatory change.
European Journal of Nuclear Medicine 06/2009; 36(11):1813-21. · 4.53 Impact Factor
