L. Chami

Prophylactic Lymph Node Dissection for Papillary Thyroid Cancer Less Than 2 cm: Implications for Radioiodine Treatment

OBJECTIVE Prophylactic neck dissection for small papillary carcinoma remains controversial. Radioiodine ablation is not recommended for tumors less than 10 mm and depends on various factors for tumors between 10 and 20 mm. The aim was to determine the effect of lymph node (LN) staging on the indication for treatment with radioiodine. PATIENTS AND METHODS We conducted a retrospective study of 115 patients presenting with papillary thyroid carcinoma less than 2 cm without ultrasonographically detectable cervical LN treated by total thyroidectomy and complete selective dissection of the central and lateral compartment. Radioiodine treatment was based on definitive pathology (tumor and LN). Follow-up was based on neck ultrasound and thyroglobulin levels. RESULTS LN were found for 41.7% of cases. Radioiodine was not used for 42% of patients with tumors less than 20 mm and no metastatic LN. Fifty-eight percent of patients were treated with radioiodine due to LN metastasis, extracapsular thyroid invasion, or unfavorable histological subtype. LN status affected the indication for radioiodine in 30.5% of cases classified as T1, 12 cases with tumors less than 10 mm but with LN metastases (who received radioiodine), and 13 cases with tumors between 10 and 20 mm but without LN metastases (who did not receive radioiodine). Definitive vocal fold paralysis and hypoparathyroidism each occurred in 0.9% of cases. At 1 yr, ultrasound was normal in all patients, and recombinant human TSH-stimulated thyroglobulin was undetectable for 97% of the patients. CONCLUSION Precise LN staging by prophylactic neck dissection for tumors initially staged T1N0 modified the indication for radioiodine ablation for 30% of patients.

Gastrointestinal Stromal Tumors Treated with Imatinib: Monitoring Response with Contrast-Enhanced Sonography

OBJECTIVE The purpose of this study was to evaluate contrast-enhanced Doppler sonography with perfusion software as a predictor of early tumor response to imatinib (Glivec) in c-kit-positive gastrointestinal stromal tumors (GISTs). SUBJECTS AND METHODS Thirty patients (59 tumors) with metastases or a recurrence from a GIST were prospectively included in a single-center imaging trial. Contrast-enhanced Doppler sonography was performed with an Aplio scanner the day before (day-1) starting oral treatment (400 mg) and at days 1, 7, 14, 60, 90, and 6 months, 9 months, and 1 year. The percentage of contrast uptake (Levovist or Sonovue) before treatment and at the different stages of follow-up was evaluated by two radiologists. Digitized quantification was performed using Photoshop software. To define the benchmark standard, all patients were rated as responders or nonresponders at 2 and 6 months by a board consisting of oncologists and radiologists who had all clinical and imaging data at their disposal. Changes in the percentage of contrast uptake at each sonographic examination were compared statistically. RESULTS A total of 185 examinations were performed. Forty-four lesions in 24 patients were completely evaluated at 2 months, and 29 lesions in 15 patients were completely evaluated at 6 months. Initial contrast uptake at day 1 was predictive of the future response. A strong correlation was found between the decline in tumor contrast uptake at days 7 and 14 and tumor response (p < 10(-4)). CONCLUSION Contrast-enhanced Doppler sonography is a noninvasive imaging technique that allows the early prediction of tumor response in c-kit-positive GIST treated with Glivec.

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

Phase I Trial of Sorafenib in Combination with IFN α-2a in Patients with Unresectable and/or Metastatic Renal Cell Carcinoma or Malignant Melanoma

Purpose: To determine the safety, maximum tolerated dose, pharmacokinetics, and efficacy, and to evaluate biomarkers, of the multikinase inhibitor sorafenib plus IFN α-2a in advanced renal cell carcinoma (RCC) or melanoma. Experimental Design: Patients received 28-day cycles of continuous, oral sorafenib twice daily and s.c. IFN thrice weekly: sorafenib 200 mg twice daily plus IFN 6 million IU (MIU) thrice weekly (cohort 1); and sorafenib 400 mg twice daily plus IFN 6 MIU thrice weekly (cohort 2); or plus IFN 9 MIU thrice weekly (cohort 3). Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and dynamic contrast-enhanced ultrasonography. Results: Thirteen patients received at least one dose of sorafenib plus IFN (12 RCC; one melanoma). The maximum tolerated dose was not reached [only one dose-limiting toxicity (grade 3 asthenia)]. Most frequently reported drug-related adverse events were grade 2 or less in severity, including fatigue, diarrhea, nausea, alopecia, and hand-foot skin reaction. One (7.7%) RCC patient achieved partial response and eight (61.5%) had stable disease (including the melanoma patient). Good responders assessed by dynamic contrast-enhanced ultrasonography had increased progression-free survival and overall survival, relative to poor responders. IFN had no effect on the pharmacokinetics of sorafenib. There were no significant changes in absolute values of lymphocytes, levels of proangiogenic cytokines, or inhibition of phosphorylated extracellular signal-regulated kinase in T cells or natural killer cells, with combination therapy. Conclusions: This sorafenib combination was well tolerated, with preliminary antitumor activity in advanced RCC and melanoma patients. There were no drug-drug interactions and the recommended dose for future studies is sorafenib 400 mg twice daily plus IFN 9 MIU.

Échographie de contraste temps réel dans la prise en charge diagnostique des lésions nodulaires hépatiques : évaluation des performances diagnostiques et de l'impact économique sur une étude multicentrique française

The recent introduction of high-end ultrasound equipment combined with recent contrast agents provides marked improvements in the characterization of focal liver lesions as previously reported by monocentric studies. The aim of the present study was to evaluate the diagnostic performance of Contrast-Enhanced Ultrasonography (CEUS) using SonoVue as well as its medico-economic value for characterization of focal liver lesions. These nodules were not characterized on previous CT or conventional sonography. This prospective multicentric study conducted in 15 French centres found diagnostic performances similar to those reported for CT and MRI, with a concordance rate of 84.5%, sensitivity greater than 80% and specificity greater than 90% for all types of lesions. Higher acceptance was found for CEUS compared to other imaging modalities. Economical assessment based on examination reimbursment and contrast agent cost showed a lower cost for contrast ultrasound versus CT and MRI. This French multicentric study confirmed the high diagnostic value of CEUS for focal liver lesion characterization and demonstrated a lower economical impact compared to other imaging modalities such as CT and MRI.

Benefits of Contrast-Enhanced Sonography for the Detection of Liver Lesions: Comparison with Histologic Findings

OBJECTIVE The objective of our study was to compare the usefulness of contrast-enhanced sonography with baseline sonography in detecting malignant liver lesions. SUBJECTS AND METHODS This prospective study included 116 patients. All patients underwent a preoperative conventional sonography examination followed by sonography after injection of contrast agent combined with the use of perfusion software (vascular recognition imaging or pulse subtraction imaging). Histopathologic analysis was the reference standard used to compare the diagnostic value of baseline sonography versus contrast-enhanced sonography. RESULTS Eighty-two patients underwent hepatic surgery, 31 did not because of disseminated lesions, and the remaining three patients did not meet inclusion criteria. Three hundred six surgically proven lesions were taken into account for comparison of the two techniques: 147 were detected on baseline sonography and 177 on contrast-enhanced sonography. Histopathologic analysis revealed 233 malignant and 73 benign lesions. Sensitivity and specificity were improved on contrast-enhanced sonography compared with baseline sonography for the detection of malignant lesions: 68.7% versus 58.8% and 67% versus 50.7%, respectively. Contrast-enhanced sonography detected 23 additional malignant lesions that had been seen as lacuna at the portal venous phase and characterized as 19 benign nodules, thus improving the performance of sonography in 13.7% of the cases. CONCLUSION Contrast injection improved the sensitivity and specificity of baseline sonography and should be performed in routine practice if hepatic surgery is being considered for the management of liver lesions.

Is 18F-Fluorodeoxyglucose–PET/CT Useful for the Presurgical Characterization of Thyroid Nodules with Indeterminate Fine Needle Aspiration Cytology?

BACKGROUND Thyroid nodules found incidentally on (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) have been shown to be malignant in 30%-50% of cases. The American Thyroid Association recommends performing fine needle aspiration cytology (FNAC) for thyroid nodules showing FDG uptake. On the other hand, the role of FDG-PET in characterizing thyroid nodules with indeterminate cytology before surgery is not clear. The goal of this study was to evaluate the role of FDG-PET/computed tomography (CT) in predicting malignancy of thyroid nodules with indeterminate FNAC and to correlate FDG uptake with pathological and ultrasonographic (US) features. METHODS Between November 2006 and October 2009, 55 patients (42 women, mean age: 50 years) planned for surgery for 56 thyroid nodules with indeterminate FNAC were prospectively included and considered for analysis. All patients underwent presurgical FDG-PET/CT (Siemens Biograph, mean FDG injected activity: 165 MBq) and neck US. Pathology of the corresponding surgical specimen was the gold standard for statistical analysis. RESULTS At pathology 34 nodules were benign, 10 were malignant (7 papillary and 3 follicular carcinomas), and 12 were tumors of uncertain malignant potential (TUMP). The median size of the thyroid nodules was 21 mm (range: 10-57). Sensitivity, specificity, positive (PPV), and negative predictive (NPV) values of FDG-PET in detecting cancer/TUMP were 77%, 62%, 57%, and 81%, respectively. In multivariate analysis, cellular atypia was the only factor predictive of FDG uptake (p<0.001). Hurthle cells and poorly differentiated components were independent predictive factors of high (≥5) SUV Max (p=0.02 and p=0.02). Sensitivity, specificity, PPV, and NPV of US in detecting cancer/TUMP were 82%, 47%, 50%, and 80%, respectively. In multivariate analysis, hypervascularization was correlated with malignancy/TUMP (p=0.007) and cystic features were correlated with benignity (p=0.03). CONCLUSION Adding FDG-PET findings to neck US provided no diagnostic benefit. The sensitivity and specificity of FDG-PET in the presurgical evaluation of indeterminate thyroid nodules are too low to recommend FDG-PET routinely.

Persistent disease and recurrence in differentiated thyroid cancer patients with undetectable postoperative stimulated thyroglobulin level

(131)I is given in differentiated thyroid cancer (DTC) without taking into account thyroglobulin (Tg) levels at the time of ablation, whereas 6-18 months later it is a major criterion for cure. This single-center retrospective study assessed the frequency and risk factors for persistent disease on postablation whole body scan (WBS) and postoperative neck ultrasonography (n-US) and for recurrent disease during the subsequent follow-up, in patients with DTC and undetectable TSH-stimulated Tg level (TSH-Tg) in the absence of Tg antibodies (TgAb) at the time of ablation. Among 1031 patients ablated, 242 (23%) consecutive patients were included. Persistent disease occurred in eight cases (3%) (seven abnormal WBS and one abnormal n-US), all with initial neck lymph node metastases (N1). N1 was a major risk factor for persistent disease. Among 203 patients with normal WBS and a follow-up over 6 months, TSH-Tg 6-18 months after ablation was undetectable in the absence of TgAb in 173 patients, undetectable with TgAb in 1 patient and equal to 1.2  ng/ml in 1 patient. n-US was normal in 152 patients and falsely positive in 3 patients. After a mean follow-up of 4 years, recurrence occurred in two cases (1%), both with aggressive histological variants. The only risk factor for recurrence was an aggressive histological variant (P = 0.03). In conclusion, undetectable postoperative TSH-Tg in the absence of TgAb at the time of ablation is frequent. In these patients, repeating TSH-Tg 6-18 months after ablation is not useful. (131)I ablation could be avoided in the absence of N1 and aggressive histological variant.

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.