Magaly Zappa

Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study

BACKGROUND Hepatocellular carcinoma (HCC) tumour spread is partly dependent on neoangiogenesis. In this open-label, multicentre, phase II trial done in Europe and Asia, sunitinib, a multitargeted tyrosine-kinase inhibitor with anti-angiogenic properties, was assessed in patients with advanced unresectable HCC. METHODS Between February and July, 2006, eligible patients were enrolled and treated with repeated cycles of oral sunitinib (50 mg/day for 4 weeks, followed by 2 weeks off treatment). The primary endpoint of this Simon two-stage phase II trial was objective response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria, with an expected response rate of 15%. This trial is registered with ClinicalTrials.gov, number NCT00247676. FINDINGS Of 37 patients enrolled, one (2.7%) patient experienced a confirmed partial response, giving an overall objective response rate of 2.7% (95% CI 0.1-14.2); on the basis of this, the trial did not proceed to the second stage. 13 (35%) of 37 patients achieved stable disease for over 3 months. Commonly observed grade 3 and 4 adverse events included thrombocytopenia (14 of 37; 37.8%), neutropenia (nine of 37; 24.3%), asthenia (five of 37; 13.5%), hand-foot syndrome (four of 37; 10.8%), and anaemia (four of 37; 10.8%). There were four deaths among the 37 patients (10.8%) that were possibly related to treatment. INTERPRETATION Sunitinib showed pronounced toxicities at a dose of 50 mg/day in patients with unresectable HCC. The response rate was low, and the study did not meet the primary endpoint based on RECIST criteria. FUNDING Pfizer Oncology.

Aiming at minimal invasiveness as a therapeutic strategy for Budd‐Chiari syndrome

The 1‐year spontaneous mortality rate in patients with Budd‐Chiari syndrome (BCS) approaches 70%. No prospective assessment of indications and impact on survival of current therapeutic procedures has been performed. We evaluated a therapeutic strategy uniformly applied during the last 8 years in a single referral center. Fifty‐one consecutive patients first received anticoagulation and were treated for associated diseases. Symptomatic patients were considered for hepatic vein recanalization; then for transjugular intrahepatic portosystemic shunt (TIPS), and finally for liver transplantation. The absence of a complete response led to the next procedure. Assessment was according to the strategy, whether procedures were technically applicable and successful. At entry, median (range) Child‐Pugh score and Clichy prognostic index were 8 (5–12), and 5.4 (3.1–7.7), respectively. A complete response was achieved on medical therapy alone in 9 patients; after recanalization in 6, TIPS in 20, liver transplantation in 9, and retransplantation in 1. Of the 41 patients considered for recanalization, the procedure was not feasible in 27 and technically unsuccessful in 3. Of the 34 patients considered for TIPS, the procedure was considered not feasible in 9 and technically unsuccessful in 4. At 1 year of follow‐up, a complete response to TIPS was achieved in 84%. One‐ and 5‐year survival from starting anticoagulation were 96% (95% CI, 90–100) and 89% (95% CI, 79–100), respectively. In conclusion, excellent survival can be achieved in BCS patients when therapeutic procedures are introduced by order of increasing invasiveness, based on the response to previous therapy rather than on the severity of the patients condition. (HEPATOLOGY 2006;44:1308–1316.)

Which magnetic resonance imaging findings accurately evaluate inflammation in small bowel Crohn's disease? A retrospective comparison with surgical pathologic analysis.

Background: The aim was to evaluate the value of magnetic resonance imaging (MRI) findings in Crohns disease (CD) in correlation with pathological inflammatory score using surgical pathology analysis as a reference method. Methods: CD patients who were to undergo bowel resection surgery underwent MR enterography before surgery. The CD pathological inflammatory score of the surgical specimens was classified into three grades: mild or nonactive CD, moderately active CD, and severely active CD; fibrosis was also classified into three grades: mild, moderate, and severe. Mural and extramural MRI findings were correlated with pathological inflammatory and fibrosis grades. Results: Fifty‐three consecutive patients were included retrospectively. The mean delay between MRI and surgery was 24 days (range 1–90, median 14). The CD pathological inflammatory score was graded as follows: grade 0 (11 patients, 21%), grade 1 (15 patients, 28%), and grade 2 (27 patients, 51%). MRI findings significantly associated with pathological inflammatory grading were wall thickness (P < 0.0001), degree of wall enhancement on delayed phase (P < 0.0001), pattern of enhancement on both parenchymatous (P = 0.02), and delayed phase, (P = 0.008), T2 relative hypersignal wall (P < 0.0001), blurred wall enhancement (P = 0.018), comb sign (P = 0.004), fistula (P < 0.0001), and abscess (P = 0.049). The inflammation score correlated with the fibrosis score (r = 0.63, P = 0.0001). Conclusions: Our study identified MRI findings significantly associated with surgical pathological inflammation. These lesions are considered potentially reversible and may be efficiently treated medically. We also showed that fibrosis was closely and positively related to inflammation. Inflamm Bowel Dis 2011

Changes in Tumor Density in Patients with Advanced Hepatocellular Carcinoma Treated with Sunitinib

Purpose: Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the efficacy of targeted therapies. In hepatocellular carcinoma (HCC) studies with sunitinib, RECIST-defined response rates are low, although hypodensity on computed tomography (CT) scans occurs more frequently. This exploratory analysis investigated tumor density as a surrogate endpoint of sunitinib activity in a phase II HCC study. Experimental Design: Patients received sunitinib 50 mg/d (4 weeks on/2 weeks off). Tumor size and density were assessed on CT scans by using RECIST and Choi criteria, the latter of which classify a partial response as a 15% or more reduction in tumor density or a 10% or more reduction in tumor size. The overall percentage volume of tumor necrosis was calculated with volumetric reconstruction. Tumor perfusion parameters were assessed by using perfusion CT scans with specific acquisition. Results: Among the 26 evaluable patients, 1 achieved a partial response and 22 had tumor stabilization by RECIST. In analysis of tumor density, 17 of 26 patients (65.4%) were responders by Choi criteria. Volumetric assessment showed major tumor necrosis (≥30% of tumor volume) in 10 of 21 patients (47.6%). Among four patients evaluated, tumor blood flow was reduced by 58.8% and blood volume by 68.4% after 4 weeks of treatment. The median time to progression (TTP) was 6.4 months. Patients with responses by Choi criteria had a significantly longer TTP (7.5 months) compared with nonresponders (4.8 months; HR = 0.33, two-sided P = 0.0182). Conclusions: Tumor density assessment suggested that radiologic endpoints in addition to RECIST may be considered to capture sunitinib activity in HCC. Clin Cancer Res; 17(13); 4504–12. ©2011 AACR.

Advanced Hepatocellular Carcinoma: Early evaluation of response to targeted therapy and prognostic value of Perfusion CT and Dynamic Contrast Enhanced-Ultrasound. Preliminary results

PURPOSE To investigate whether there is any correlation between standard endpoints and tumor perfusion measurements with Perfusion CT and Dynamic Contrast-Enhanced Ultrasonography (DCE-US) in patients with advanced Hepatocellular Carcinoma (HCC) treated with targeted therapy. MATERIALS AND METHODS Nineteen patients were evaluated during targeted therapy (sorafenib n=16, sunitinib n=3). Changes in tumor perfusion measurements between baseline and month 1 were assessed and compared using RECIST progression criteria at month 2. RESULTS Median time to progression according to RECIST was 117 days and median time to death was 208 days. Perfusion CT values before treatment were significantly increased in HCC compared to the surrounding liver (n=17, P<.02). Eleven patients received complete examinations with both techniques at baseline and month 1. A non-significant decrease was found in all Perfusion CT values between RECIST nonprogressors (n=7) and progressors (n=4): mean Blood Volume: -27.9 vs. -11.1% and mean Blood Flow: -25.0 vs. -11.7% respectively. With DCE-US, opposite changes were found (mean Area Under the Curve AUC: -38.3 vs. 436.3%). RECIST progression at month 2 was significantly correlated with a threshold 40% decrease in AUC (P=.015). None of the patients with a decrease in AUC≥40% was a progressor at month 2. CONCLUSION Despite perfusion changes with both Perfusion CT and DCE-US in patients receiving treatment, only DCE-US at month 1 (with a decrease in the AUC of more than 40%) predicted non-progression at month 2 and may be a potential surrogate marker of tumor response during targeted therapy.

Ki-67 index, tumor differentiation, and extent of liver involvement are independent prognostic factors in patients with liver metastases of digestive endocrine carcinomas

The prognosis remains ill-defined in patients with liver metastases of well-differentiated (WD) digestive endocrine carcinomas (DEC) with high Ki-67 index. The objectives of this study were to determine whether Ki-67 index, tumor differentiation, and extent of liver involvement are independent prognostic factors in patients with DEC, and whether chemotherapy commonly used in patients with poorly differentiated (PD) carcinomas might be applied to those with high Ki-67 index but well-differentiated DEC. Sixty-three patients with DEC metastatic to the liver were retrospectively studied and divided into three prognostic groups. Group 1 comprised patients with well-differentiated carcinomas and Ki-67 index<15% (n=28), group 2 comprised those with well-differentiated carcinomas and Ki-67 index≥15% (n=17), and group 3 comprised those with poorly differentiated carcinomas (n=18). Therapeutic strategy was decided in accordance to guidelines, and tumoral response rate was assessed by computed tomography scan (RECIST). Prognostic factors were determined by uni/multivariate analysis. The 5-year survival rates were 89, 36, and 6% in groups 1, 2, and 3 respectively (P<0.001). Multivariate analysis showed that Ki-67 index≥15%, poor tumor differentiation, and large liver tumor burden were independent predictors of poorer survival. Disease control rates after etoposide-cisplatin were 50 and 53% in groups 2 and 3 respectively (NS). In conclusion, Ki-67 index, tumor differentiation, and extent of liver involvement are independent prognostic factors in patients with liver metastases of DEC. Patients with well-differentiated carcinomas with high Ki-67 index (≥15%) have intermediate prognosis and a similar response rate to the etoposide-cisplatin combination as those with poorly differentiated carcinomas.

T4 colorectal cancer: is laparoscopic resection contraindicated?

Aim  T4 colorectal cancer remains a contraindication for laparoscopy. It is argued that the risk of incomplete resection could be higher than in open surgery. Furthermore, difficulty in dissection could lead to a very high rate of conversion. There is little information on this. The study aimed at assessing feasibility and operative and oncologic results of laparoscopic resection for T4 colorectal cancer.

Hepatic Arterial Embolization versus Chemoembolization in the Treatment of Liver Metastases from Well-Differentiated Midgut Endocrine Tumors: A Prospective Randomized Study

Background: Liver surgery is the best treatment for endocrine liver metastases, but it is often impossible due to diffuse disease. Systemic chemotherapy is poorly effective. Hepatic arterial embolization (HAE) and chemoembolization (HACE) have shown efficacy but have never been compared. Patients and Methods: Patients with progressive unresectable liver metastases from midgut endocrine tumors were randomly assigned to receive HAE or HACE (two procedures at 3-month interval). The primary end point was the 2-year progression-free survival (PFS) rate. Secondary end points were response rates, overall survival, and safety. Results: Twelve patients were assigned to receive HACE and 14 to receive HAE. The patient characteristics were well matched across the treatment arms. The 2-year PFS rates were 38 and 44% in the HACE and HAE arms, respectively (p = 0.90). Age, gender, previous resection of the primary tumor or liver metastases, extent of liver involvement, and concomitant treatment with somatostatin analogues were not associated with changes in PFS, whereas elevated baseline urinary 5-HIAA and serum chromogranin A levels were associated with shorter PFS. The 2-year overall survival rates were 80 and 100% in the HACE and HAE arms, respectively (p = 0.16). The disease control rate on CT scan was 95%. Grade 3 toxicity occurred in 19% of patients, with no treatment-related deaths and no differences in the treatment arms. Conclusion: HACE and HAE are safe and permit tumor control in 95% of patients with progressive liver metastases from midgut endocrine tumors. The 2-year PFS was not higher among patients receiving HACE, not favoring the hypothesis of an additive efficacy of arterial chemotherapy or embolization alone.

FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide–platinum combination in patients with neuroendocrine carcinomas grade 3

Patients with neuroendocrine carcinomas (NECs) grade 3 have a poor prognosis. Etoposide-platinum combination is the standard chemotherapy but the role of a second-line therapy remains unknown. Irinotecan alone or in combination has shown some efficacy in patients treated for small cell lung cancer which had pathological similarities with neuroendocine tumors. The aim of this study is to determine safety and efficacy of the FOLFIRI regimen in patients with NECs grade 3 after failure of etoposide-platinum combination. This study was retrospective, including patients with NECs grade 3 and treated with the FOLFIRI regimen after progression or toxicity of etoposide-platinum combination in first-line. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≥3 and/or serum alkaline phosphatase ≥5×upper limit of normal value (ULN) and/or bilirubin ≥1.5×ULN were excluded. Among 39 patients who failed etoposide-platinum combination, 19 (49%; 12 women, median age 53 (29-78) years) received the FOLFIRI regimen with a median number of 6 (1-16) courses. Six patients (31%) had at least one episode of grades 3-4 toxicity (neutropenia, n=3; diarrhea, n=3) without toxic death. Six patients (31%) had objective response, 6 (31%) stable disease, and 7 (38%) tumor progression. Median progression-free survival under FOLFIRI was 4 months. Overall survival was 18 vs 6.8 months in noneligible patients. FOLFIRI regimen is a safe and potentially efficient chemotherapy given as second-line in patients with NECs grade 3 who remain in good condition and with correct liver tests after failure of etoposide-platinum combination. These results should be confirmed in a future prospective study.

Predictive factors for failure of pelvic arterial embolization for postpartum hemorrhage.

To assess the efficacy of pelvic embolization in women with postpartum hemorrhage (PPH) and to determine factors associated with embolization failure.