Baya Benatsou

Advanced Hepatocellular Carcinoma: Early Evaluation of Response to Bevacizumab Therapy at Dynamic Contrast-enhanced US with Quantification—Preliminary Results

PURPOSE To investigate whether there is any correlation between standard efficacy endpoints-specifically, tumor response, progression-free survival, and overall survival-and tumor perfusion parameters measured by using dynamic contrast material-enhanced ultrasonography (US) in patients with advanced hepatocellular carcinoma (HCC) treated with bevacizumab. MATERIALS AND METHODS The institutional review board approved the study, and all patients provided written informed consent before their enrollment. Between June 3, 2005, and September 28, 2007, 42 patients (33 men, nine women; median age, 62 years; age range, 23-84 years) participated in this phase II study of single-agent bevacizumab treatment. Tumor response (based on RECIST [response evaluation criteria in solid tumors]) at 2 months was assessed in 37 patients, and progression-free survival and overall survival were assessed in all 42 patients. Dynamic contrast-enhanced US (ie, dynamic US) was performed before treatment (day 0); on days 3, 7, 14, and 60 after treatment; and every 2 months thereafter. Tumor perfusion parameters were estimated quantitatively from contrast material uptake curves constructed from raw linear data. The changes in dynamic US functional parameters between day 0 and the later time points were compared between treatment responders and nonresponders by using nonparametric tests. Given multiple comparisons, P < .001 indicated significance. RESULTS The percentage decrease in several dynamic US parameters between day 0 and day 3 showed trends toward correlation with (a) tumor response in terms of total area under the time-intensity curve (AUC) (P = .02), AUC during wash in (P = .04), AUC during washout (P = .02), and time to peak intensity (P = .03); (b) progression-free survival in terms of time to peak intensity (P = .028); and (c) overall survival in terms of AUC (P = .002) and AUC during washout (P = .003). CONCLUSION Dynamic US can be used to quantify dynamic changes in tumor vascularity as early as 3 days after bevacizumab administration in patients with HCC. These early changes in tumor perfusion may be predictive of tumor response at 2 months, progression-free survival, and overall survival, and they may be potential surrogate measures of the effectiveness of antiangiogenic therapy in patients with HCC.

Metastatic Renal Cell Carcinoma Treated with Sunitinib: Early Evaluation of Treatment Response Using Dynamic Contrast-Enhanced Ultrasonography

Purpose: To determine the utility of dynamic contrast-enhanced ultrasonography (DCE-US) as a prognostic tool for metastatic renal cell carcinoma patients receiving sunitinib and to identify DCE-US parameters that correlate with early treatment response. Experimental Design: Thirty-eight patients received 50 mg/d sunitinib on schedule 4/2 (4 weeks on followed by 2 weeks off treatment). After two cycles, response evaluation criteria in solid tumors were used to classify patients as responders or nonresponders. DCE-US evaluations were done before treatment and at day 15; variations between days 0 and 15 were calculated for seven DCE-US functional parameters and were compared for responders and nonresponders. The correlation between DCE-US parameters and disease-free survival (DFS) and overall survival (OS) was assessed. Results: The ratio between DCE-US examinations at baseline and day 15 significantly correlated with response in five of the seven DCE-US parameters. Two DCE-US parameters (time to peak intensity and slope of the wash-in) were significantly associated with DFS; time to peak intensity was also significantly associated with OS. Conclusions: DCE-US is a useful tool for predicting the early efficacy of sunitinib in metastatic renal cell carcinoma patients. Robust correlations were observed between functional parameters and classic assessments, including DFS and OS. Clin Cancer Res; 16(4); 1216–25

Évaluation précoce des traitements anti-angiogéniques par échographie dynamique de contraste

Early functional imaging evaluation of targeted treatments in oncology is of major importance. Dynamic contrast enhanced US is now recognized as a functional imaging technique able to evaluate new antiangiogenic drugs targeting superficial and deep seated lesions. This evaluation is based on an analysis of the curve of signal intensity over time after injection of the contrast agent. The availability of quantification software allows objective quantification of tumor perfusion parameters from linear raw data, prior to logarithmic signal compression, including maximum intensity of enhancement, mean transit time, time to peak, and wash-in slope coefficient. Dynamic contrast enhanced US, a sensitive, reproducible and readily available technique, allows early prediction of tumor response to treatment based on changes in vascularity, before morphological changes (RECIST) become apparent.

Study of dynamic contrast-enhanced ultrasound (DCE-US) for the early evaluation in patients included in phase II treated with TKI 258 in renal cell carcinoma.

e13588 Background: To determine the best timing for the early assessment of a functional parameter calculated with DCE-US in order to rapidly distinguish poor responders from good responders among patients treated with TKI 258 in phase II. METHODS All patients had an examination just before the start of TKI 258 (D-1) and at D7, D14, D 30, D 60 and D 120. Each examination included a bolus injection of 4.8 ml of Sonovue (Bracco) and raw linear data were recorded over 3 minutes with an Aplio (Toshiba). The raw linear data were analyzed with a mathematical model (patent PCT/IB2006/003742) to evaluate one parameter (the area under the curve (AUC) correlated with the blood volume) characterizing the tumor perfusion curve. Response to treatment was evaluated with RECIST criteria with scanographic evaluations. Complete or partial responses and stabilization were classified as successes and progression as treatment failure. RESULTS A total of 7 patients were included for the DCE-US evaluation. According to RECIST criteria, the median time to event of 3 poor responders was 4 months and the time to event of the 4 good responders was always more than 12 months. 36 DCE-US examinations were performed. Among good responders: The median variation in the AUC between baseline and D7, 14, 30, 60 and D 120 was -85%, -55%, -77%, -59% and -81% respectively. CONCLUSIONS Our results confirm the interest of DCE-US for monitoring TKI 258 in metastatic RCC. The dramatic decrease in the AUC started from D7 after the beginning of treatment.

Study of dynamic contrast-enhanced ultrasound (DCE-US) for the early evaluation of imatinib.

10062 Background: To determine the best timing for the early assessment of a functional parameter calculated with DCE-US in order to select rapidly poor responders from good responders. METHODS All patients had an examination just before the start of imatinib (D-1) and at D7, D14, D30 and D60. Each examination included a bolus injection of 4.8 ml of Sonovue (Bracco) and raw linear data were recorded over 3 minutes with an Aplio (Toshiba). The raw linear data were analyzed with a mathematical model (patent PCT/IB2006/003742) to evaluate one parameter (the area under the curve (AUC) correlated with the blood volume) characterizing the tumor perfusion curve. Response to treatment was evaluated every 2 months with RECIST criteria with scanographic evaluations. Complete or partial responses and stabilization were classified as successes and progression as treatment failure. RESULTS Since March 2005, 26 patients have been included. The median time to event of of the 6 poor responders was 2 months. The median follow-up of the 20 good responders was 28 months. 109 DCE-US examinations have been performed. Among poor responders: The median variation in the AUC between baseline and D7, 14, 30 and 60 was -19%, -10%, +46% and +86 respectively. In good responders: The variation in the AUC between baseline and D7, 14, 30 and 60 was -20%, -83%, -83% and -88 % respectively. CONCLUSIONS Our results confirm the interest of DCE-US for monitoring imatinib in GIST. The best timing using the AUC is D15 after the beginning of treatment.

DIG-WS-48 Evaluation precoce par echographie de contraste des patients atteints d’un carcinome hepatocellulaire traites par bevacizumab

Objectifs Determiner precocement les parametres de perfusion par echographie de contraste avec quantification (DCE-US) permettant de predire la reponse a 4 mois chez des patients avec carcinome hepatocellulaire traites par bevacizumab. Materiels et methodes Les DCE-US ont ete realisees chez 42 patients : avant Tt, J3, J8, J15,2mois puis tous les 2 mois, avec injection du Sonovue® (Bracco) en bolus et en utilisant le mode VRI (Aplio, Toshiba). Les courbes de perfusion ont ete acquises apres modelisation a partir des donnees lineaires brutes avec le logiciel CHI-Q. Sept parametres ont ete calcules : pic d’intensite, pente du wash-in, aire totale sous la courbe, aires du wash-in et du wash-out, temps de montee et temps de transit moyen. Ces parametres ont ete compares a la reponse RECIST a 4 mois. Resultats Au total, 262 DCE-US ont ete realisees chez 22 bons et 20 mauvais repondeurs. Les valeurs medianes de 5 parametres se sont modifiees des J3 : pic d’intensite, aire totale sous la courbe, aires du wash-in et du wash-out, pente du wash-in. En revanche, le temps de transit moyen et le temps de montee ne se sont pas modifies au cours du temps. Conclusion La DCE-US permet de predire la reponse a 4 mois des J3.