Showing papers by "Armando Santoro published in 2011"

Safety and Efficacy of Sorafenib in Patients with Hepatocellular Carcinoma (HCC) and Child-Pugh A versus B Cirrhosis.

Abstract: Background We performed a retrospective analysis of data from a phase II study evaluating sorafenib in patients with advanced hepatocellular carcinoma (HCC) to assess differences in safety and efficacy based on Child-Pugh (CP) status (A/B) Methods Patients received sorafenib 400 mg PO bid We analyzed safety, pharmacokinetic (PK), and efficacy data in the two CP groups Results Ninety-eight patients were CP A; 38 were CP B, with a median duration of therapy of 4 and 18 months, respectively Grade 3/4 adverse events in the CP A and B groups, respectively, included hyperbilirubinemia (14% and 53%), ascites (3% and 5%), and encephalopathy (3% and 13%) Median overall survival (OS) in the CP A group was 95 months, compared with 32 months in the CP B population Responses were limited in both groups AUC and C(max) values were comparable between the two groups Conclusions Due to the lack of randomization against placebo or no therapy in this study, it is unclear if the more frequent worsening of liver cirrhosis and outcome of CP B patients are drug related or due to disease progression, or both As expected, outcome was poorer in patients with CP B than in those with CP A cirrhosis The hyperbilirubinemia seen in both groups may be at least partly related to inhibition of UGT1A1 by sorafenib PK profiles were similar in the two groups More data are needed to confirm and more fully understand the safety and efficacy of sorafenib in patients with advanced HCC and CP B cirrhosis

Thymidylate Synthase and Excision Repair Cross-Complementing Group-1 as Predictors of Responsiveness in Mesothelioma Patients Treated with Pemetrexed/Carboplatin

Abstract: Purpose: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients. Results: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy ( P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease ( P = 0.022), shorter PFS ( P P TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome. Conclusions: In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted. Clin Cancer Res; 17(8); 2581–90. ©2011 AACR .

Retroperitoneal sarcoma: is it time to change the surgical policy?

Abstract: Complete tumor resection is the mainstay of treatment for retroperitoneal sarcoma (RPS), but the size and quality of surgical margins for radical resection in RPS are unknown. They are believed to be pushing tumors, but recently, aggressive surgical policies leading to multivisceral resection have seemed to suggest better local control compared with simple tumor resection. We analyzed a single-institution series of RPS to provide information useful to surgical decision-making. From 1996 to 2008, 77 patients referred to our institution underwent surgery for primary RPS. Thirty tumors were classified as liposarcoma, and 20 as leiomyosarcoma. Potential prognostic factors were tested retrospectively. Number and pathologic status of resected organs were assessed. 151 organs were resected. Ninety-two were involved by the tumor (60.9%). Liposarcoma involved 48 of 77 organs resected for this histotype (62.3%). Infiltrative pattern was observed in 39/92 organs, and expansive pattern in 53/92 viscera. The infiltrative pattern was more often observed in leiomyosarcoma and non-lipogenic tumors. The expansive pattern was more often observed in liposarcoma. Psoas was the organ most often involved by infiltrative pattern (12/14); the kidney was the organ most often involved by expansive pattern (19/28). 80% of patients had at least one viscera infiltrated by the tumor. This series, in which an aggressive surgical policy was adopted along with extensive pathologic sampling, shows that RPS has a high rate of viscera infiltration. This growth pattern is characteristic of well-differentiated liposarcoma too. These pathologic data should be considered when planning surgical strategy.

Clinical outcome of hypofractionated stereotactic radiotherapy for abdominal lymph node metastases.

Abstract: Purpose We report the medium-term clinical outcome of hypofractionated stereotactic body radiotherapy (SBRT) in a series of patients with either a solitary metastasis or oligometastases from different tumors to abdominal lymph nodes. Methods and Materials Between January 2006 and June 2009, 19 patients with unresectable nodal metastases in the abdominal retroperitoneal region were treated with SBRT. Of the patients, 11 had a solitary nodal metastasis and 8 had a dominant nodal lesion as part of oligometastatic disease, defined as up to five metastases. The dose prescription was 45 Gy to the clinical target volume in six fractions. The prescription had to be downscaled by 10% to 20% in 6 of 19 cases to keep within dose/volume constraints. The first 11 patients were treated with three-dimensional conformal techniques and the last 8 by volumetric intensity-modulated arc therapy. Median follow-up was 1 year. Results Of 19 patients, 2 had a local progression at the site of SBRT; both also showed concomitant tumor growth at distant sites. The actuarial rate of freedom from local progression was 77.8% ± 13.9% at both 12 and 24 months. Eleven patients showed progressive local and/or distant disease at follow-up. The 12- and 24-month progression-free survival rates were 29.5% ± 13.4% and 19.7% ± 12.0%, respectively. The number of metastases (solitary vs. nonsolitary oligometastases) emerged as the only significant variable affecting progression-free survival ( p Conclusions Stereotactic body radiotherapy for metastases to abdominal lymph nodes was shown to be feasible with good clinical results in terms of medium-term local control and toxicity rates. Even if most patients eventually show progressive disease at other sites, local control achieved by SBRT may be potentially significant for preserving quality of life and delaying further chemotherapy.

Preclinical Assessment of Volumetric Modulated Arc Therapy for Total Marrow Irradiation

Abstract: Purpose A preclinical investigation was undertaken to explore a treatment technique for total marrow irradiation using RapidArc, a volumetric modulated arc technique. Materials and Methods Computed tomography datasets of 5 patients were included. Plans with eight overlapping coaxial arcs were optimized for 6-MV photon beams. Dose prescription was 12 Gy in 2 Gy per fraction, normalized so that 100% isodose covered 85% of the planning target volume (PTV). The PTV consisted of the whole skeleton (including ribs and sternum), from the top of the skull to the medium distal third of the femurs. Planning objectives for organs at risk (OARs) were constrained to a median dose Results The median total body volume in the study was 57 liters (range, 49–81 liters), for an average diameter of 47 cm (range, 46–53 cm) and a total length ranging from 95 to 112 cm. The median PTV volume was 6.8 liters (range, 5.8–10.8 liters). The mean dose to PTV was 109% (range, 107–112%). The global mean of median dose to all OARs was 4.9 Gy (range, 4.5–5.1 Gy over the 5 patients). The individual mean of median doses per organ ranged from 2.3 Gy (oral cavity) to 7.3 Gy (bowels cavity). Preclinical quality assurance resulted in a mean gamma agreement index of 94.3 ± 5.1%. The delivery time measured from quality assurance runs was 13 minutes. Conclusion Sparing of normal tissues with adequate coverage of skeletal bones was shown to be feasible with RapidArc. Pretreatment quality assurance measurements confirmed the technical agreement between expected and actually delivered dose distributions, suggesting the possibility of incorporating this technique in the treatment options for patients.

Impact of ABCG2 polymorphisms on the clinical outcome and toxicity of gefitinib in non-small-cell lung cancer patients.

Abstract: Aims: The current study investigates whether or not functional polymorphisms in the ATP-binding cassette transporter gene ABCG2 might affect gefitinib activity and/or toxicity in non-small-cell lung cancer (NSCLC) patients. Materials & methods: Towards this end, ABCG2 polymorphisms and expression were assessed in DNA and tumors from 94 NSCLC patients treated with gefitinib, whereas their associations with toxicity/response and time-to-progression/overall survival were evaluated using Pearson-χ2 and log-rank-test, respectively. Results: Patients carrying an ABCG2 -15622T/T genotype or harboring at least one TT copy in the ABCG2 (1143C/T, -15622C/T) haplotype developed significantly more grade 2/3 diarrhea (p < 0.01). No associations were found between polymorphisms and outcome. Consistently, ABCG2 protein levels in tumors were not significantly different between patients harboring different ABCG2 variants. Conclusion: The ABCG2 -15622C/T polymorphism and ABCG2 (1143C/T, -15622C/T) haplotype resulted in a g...

Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: Molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin

Abstract: Although pemetrexed, a potent thymidylate synthase (TS) inhibitor, enhances the cytoytoxic effect of platinum compounds against malignant pleural mesothelioma (MPM), novel combinations with effective targeted therapies are warranted. To this end, the current study evaluates new targeted agents and their pharmacological interaction with carboplatin–pemetrexed in human MPM cell lines. We treated H2052, H2452, H28 and MSTO-211H cells with carboplatin, pemetrexed and targeted compounds (gefitinib, erlotinib, sorafenib, vandetanib, enzastaurin and ZM447439) and evaluated the modulation of pivotal pathways in drug activity and cancer cell proliferation. Vandetanib emerged as the compound with the most potent cytotoxic activity, which interacted synergistically with carboplatin and pemetrexed. Drug combinations blocked Akt phosphorylation and increased apoptosis. Vandetanib significantly downregulated epidermal growth factor receptor (EGFR)/Erk/Akt phosphorylation as well as E2F-1 mRNA and TS mRNA/protein levels. Moreover, pemetrexed decreased Akt phosphorylation and expression of DNA repair genes. Finally, most MPM samples displayed detectable levels of EGFR and TS, the variability of which could be used for patients’ stratification in future trials with vandetanib–pemetrexed–carboplatin combination. Vandetanib markedly enhances pemetrexed–carboplatin activity against human MPM cells. Induction of apoptosis, modulation of EGFR/Akt/Erk phosphorylation and expression of key determinants for pemetrexed and carboplatin activity contribute to this synergistic interaction, and, together with the expression of these determinants in MPM samples, warrant further clinical investigation.

Percutaneous vertebral augmentation in metastatic disease: state of the art.

Abstract: Improvements in diagnosis and treatment have prolonged cancer survival, with a consequent increase in the incidence of spinal metastases and vertebral compression fractures with associated axial pain, progressive radiculomyelopathy, and mechanical instability. Pain relief in malignant vertebral compression fractures is key to achieving a better quality of life in patients under palliative care. The gold standard for pain relief is nonsteroidal anti-inflammatory drugs and opioids. Nonresponsive cases are then treated with radiotherapy, which may require 2-4 weeks to take effect and in most cases does not provide complete pain relief. Percutaneous vertebroplasty and percutaneous kyphoplasty can in particular give relief in patients with vertebral body compression fractures that do not cause neurological deficits but severely compromise quality of life because of intractable pain.

Letrozole plus GnRH analogue as preoperative and adjuvant therapy in premenopausal women with ER positive locally advanced breast cancer

Abstract: Patients with large ER positive tumors candidate to preoperative chemotherapy may also benefit from a concurrent endocrine intervention, but this issue has been scarcely investigated due to concerns arising from unfavorable results emerged from an adjuvant trial of concurrent tamoxifen and chemotherapy. We retrospectively investigated the activity of letrozole plus GnRH analogue (GnRH-a) administered concurrently with preoperative chemotherapy and as adjuvant treatment in premenopausal women with locally advanced ER positive breast cancer consecutively admitted at the European Institute of Oncology. Results were compared with those of a non-randomized unmatched control group of premenopausal women with locally advanced ER positive breast cancer receiving preoperative chemotherapy, followed by tamoxifen and GnRH-a after surgery. Primary endpoints were pathological complete response (pCR) rate, decrease of Ki67 and disease free survival (DFS). One-hundred and nineteen women constituted the study group, while 95 patients served as controls. The pCR rate was 5.0 vs 1.1% in the study and control group, respectively. A statistically significant greater suppression of Ki67 was observed in patients receiving chemoendocrine therapy as compared with controls (P = 0.003). At a median follow up of 59 months, 26 events occurred in the chemoendocrine group and 48 in the control group. Five-year DFS was 78 vs 41% in the study and in the control group, respectively [adjusted HR 0.46, 95% CI 0.27-0.79, P = 0.0047]. The concurrent administration of letrozole and GnRH-a with preoperative chemotherapy was highly effective in premenopausal women with large ER positive breast cancer in terms of decreased proliferation and of improved DFS. Randomized studies are warranted to establish the role of the addition of endocrine therapy to chemotherapy as standard preoperative approach for ER positive locally advanced breast cancer as well as of letrozole in combination with GnRH-a for the treatment of premenopauasal women with early breast cancer.

Optimized management of advanced hepatocellular carcinoma: Four long-lasting responses to sorafenib

Abstract: The therapeutic options for hepatocellular carcinoma (HCC) have been so far rather inadequate. Sorafenib has shown an overall survival benefit and has become the new standard of care for advanced HCC. Nevertheless, in clinical practice, some patients are discontinuing this drug because of side effects, and misinterpretation of radiographic response may contribute to this. We highlight the importance of prolonged sorafenib administration, even at reduced dose, and of qualitative and careful radiographic evaluation. We observed two partial and two complete responses, one histologically confirmed, with progression-free survival ranging from 12 to 62 mo. Three of the responses were achieved following substantial dose reductions, and a gradual change in lesion density preceded or paralleled tumor shrinkage, as seen by computed tomography. This report supports the feasibility of dose adjustments to allow prolonged administration of sorafenib, and highlights the need for new imaging criteria for a more appropriate characterization of response in HCC.

Detection of somatostatin receptor subtypes 2 and 5 by somatostatin receptor scintigraphy and immunohistochemistry: clinical implications in the diagnostic and therapeutic management of gastroenteropancreatic neuroendocrine tumors.

Abstract: Aims and background Somatostatin receptor scintigraphy (SRS) is the standard method for the detection of somatostatin receptors (SSTRs). It is commonly used in gastroenteropancreatic neuroendocrine tumor (GEP-NET) staging, and represents the criterion of choice for treatment with somatostatin (SST) analogs. Immunohistochemistry (IHC) was reported as a reliable method for the detection of SSTRs with theoretically superior sensitivity over SRS. Methods and study design We retrospectively analyzed the sensitivity and specificity of IHC in the detection of SSTRs in a cohort of consecutive patients with GEP-NETs attending our Institute from 1997 to 2007. IHC analysis was restricted to SSTR2 and SSTR5, and the results were interpreted according to two different scoring systems. SRS was used as the gold standard. Results. Forty-four patients were enrolled; 24 (55%) had foregut carcinoids, 9 (20%) midgut carcinoids, 2 (5%) hindgut carcinoids, and 9 (20%) had GEP-NETs of unknown primary sites. A high concordance rate between IHC and SRS was shown, irrespective of the IHC scoring system applied (73% and 70%). The sensitivity of IHC was 89.3% and 78.6% and the specificity 43.8% and 50%, depending on the scoring system used. Conclusions Although SSTR2 was shown to be expressed by IHC in up to 50% of tumors not visualized by SRS, SRS still remains the method of choice in the diagnostic and therapeutic management of GEP-NETs. More pathological and clinical data are needed to properly understand the clinical relevance of immunohistochemical detection of SSTR expression in the absence of tumor uptake at SRS.

Retroperitoneal Sarcoma: Is It Time to Change the Surgical Policy?

Abstract: Background. Complete tumor resection is the mainstay of treatment for retroperitoneal sarcoma (RPS), but the size and quality of surgical margins for radical resection in RPS are unknown. They are believed to be pushing tumors, but recently, aggressive surgical policies leading to multivisceral resection have seemed to suggest better local control compared with simple tumor resection. We analyzed a single-institution series of RPS to provide information useful to surgical decision-making. Methods. From 1996 to 2008, 77 patients referred to our institution underwent surgery for primary RPS. Thirty tumors were classified as liposarcoma, and 20 as leiomyosarcoma. Potential prognostic factors were tested retrospectively. Number and pathologic status of resected organs were assessed. Results. 151 organs were resected. Ninety-two were involved by the tumor (60.9%). Liposarcoma involved 48 of 77 organs resected for this histotype (62.3%). Infiltrative pattern was observed in 39/92 organs, and expansive pattern in 53/92 viscera. The infiltrative pattern was more often observed in leiomyosarcoma and non-lipogenic tumors. The expansive pattern was more often observed in liposarcoma. Psoas was the organ most often involved by infiltrative pattern (12/14); the kidney was the organ most often involved by expansive pattern (19/28). 80% of patients had at least one viscera infiltrated by the tumor. Conclusions. This series, in which an aggressive surgical policy was adopted along with extensive pathologic sampling, shows that RPS has a high rate of viscera infiltration. This growth pattern is characteristic of well-differentiated liposarcoma too. These pathologic data should be considered when planning surgical strategy.

Fatal Infusion Reaction to Cetuximab: The Need for Predictive Risk Factors and Safer Patient Selection

Abstract: Case Report A 63-year-old man with a history of metastatic colon cancer and a wild-type KRAS genotype visited our institution as an outpatient. The patient had previously received oxaliplatinand irinotecan-based chemotherapy and pulmonary resection. At our institution, he received the first course of a combined irinotecan and cetuximab treatment. He was in excellent health with no significant complaints or tumor-related symptoms. His medical history was uninformative, and he reported no comorbidity and no known allergies. A few minutes before the infusion, the patient had normal vital signs (including blood pressure and heart rate) and a normal blood count. The protocol at our institution required premedication with chlorpheniramine (10 mg intravenously [IV]), dexamethasone (8 mg IV), and atropine (0.25 mg subcutaneously) before the administration of cetuximab (400 mg/m IV infusion delivered over 120 minutes) and irinotecan (180 mg/m IV infusion delivered over 90 minutes). A few minutes after this treatment finished, the patient began to exhibit sialorrhea, sweating, and diarrhea, which was indicative of irinotecaninduced cholinergic syndrome. However, despite the administration of atropine (0.5 mg subcutaneously), the symptoms rapidly deteriorated. He experienced dyspnea, expectoration of a white, frothy mucus, and initial decrease in the level of consciousness. The patient’s oxygen saturation fell to 70% in ambient air, and bilateral rales and ronchi were detected on chest auscultation. The patient was admitted to the intensive care unit. He underwent intubation and mechanical ventilation with supplemental oxygen, but he rapidly developed marked respiratory distress with severe acidosis. A first chest x-ray performed two hours after the drug infusion showed bilateral pulmonary infiltrates and initial lower pulmonary lobes hypoventilation. These findings were particularly noted in the lower pulmonary lobes (Fig 1). A subsequent chest x-ray performed three hours later showed a significant worsening of pulmonary hypoventilation and the likely appearance of right pleural effusion (Fig 2). No left ventricular dysfunction was demonstrated on transthoracic echocardiography. Ten hours after the onset of symptoms

Surgery Followed by Radiotherapy for the Treatment of Metastatic Epidural Spinal Cord Compression From Breast Cancer

Abstract: Study design Retrospective analysis of breast cancer patients with metastatic epidural spinal cord compression (MESCC) undergoing surgery and radiation therapy. Objective To assess feasibility and clinical outcome of multidisciplinary approach in breast cancer patients with MESCC. Summary of background data Studies so far published in the setting of surgery and/or radiotherapy in the management of MESCC usually included many malignancies, without considering the different primary histology. However, when looking at prognostic variables of this therapy, histological type comes out as a major determinant of outcome. Methods Twenty-three patients with symptomatic MESCC from breast cancer treated between January 2004 and April 2009 were included in this analysis. Twenty-six surgical procedures followed by radiotherapy were performed. Clinical outcome and local recurrence was evaluated by modified visual analog scale for pain, Frankel scale for neurologic deficit, and magnetic resonance imaging or computed tomography scans. Twenty-three cases (88.4%) had back pain before treatment with a visual analog scale score 6 or greater; neurologic deficit (FS A-D) was present in 19 cases (65.5%). Results Complete remission of pain, lasting until death or progression of disease in another skeletal site, was obtained in 25/26 cases (96.1%). All patients had complete recovery of neurologic deficit. No major morbidity occurred. No patients had recurrence in the site of treatment. Median survival was 36 months (range, 3-60) and overall survival at one, three, and five years was 70%, 42%, and 34%, respectively. Conclusion We provided evidence of surgery and radiotherapy to be feasible with limited morbidity. Clinical outcome has been highly satisfactory in terms of pain and local disease control. The discussion of each case within a multidisciplinary team is of central importance in defining the most appropriate therapeutic approach.

Randomized phase II study of danusertib (D) in second-line metastatic castration-resistant prostate cancer (CRPC).

Abstract: 4628 Background: D is a small molecule that inhibits Aurora kinases, proteins regulating mitosis, implicated in tumorigenesis and overexpressed in prostate cancer. After D administration, tumor reg...

Phase I and pharmacodynamic study of high-dose NGR-hTNF in patients with solid tumors.

Abstract: 2522 Background: NGR-hTNF consists of tumor necrosis factor fused with the peptide NGR, which selectively binds to CD13 overexpressed on tumor blood vessels. Maximum tolerated dose (MTD) of NGR-hTN...

Treatment of malignant pleural mesothelioma: current status and future directions

Abstract: Malignant pleural mesothelioma (MPM) is an aggressive tumor, with a poor prognosis and an increasing incidence as a result of widespread exposure to asbestos. Approximately 80% of MPM can be attributed to asbestos fiber exposure. Surgery and radiotherapy have a limited role in highly selected patients and systemic therapy is the only potential treatment option for the majority of patients. Unfortunately, despite some definite activity of the novel antifolates such as pemetrexed and raltitrexed, the results even in combination with platinating agents are still modest. The median survival of these patients remains of approximately 1 year. Improvements in surgical and radiotherapy techniques, in tumor assessment and staging and in the knowledge of the major molecular pathways involved in MPM are needed to increase the survival of these patients.