Riccardo Ragona

Stereotactic body radiation therapy for early stage non-small cell lung cancer: Results of a prospective trial

Patients affected with early stage (IA-IB) non-small cell lung cancer (NSCLC), deemed medically inoperable, are usually treated by conventional 3D-CRT, with poor results in terms of local tumour control and survival. Hypofractionated stereotactic body radiation therapy (SBRT) appears to be a valid alternative option, with high rates of local control and promising survival rates according to recent reported series. We herein report the final results of a prospective phase II trial of SBRT in 62 stage I NSCLC patients, homogeneously treated with three fractions of 15Gy each, given every other day during a 1 week time, up to a total dose of 45Gy; dose was prescribed to the 80%-isodose encompassing planning target volume. Patients were immobilized in a dedicated stereotactic body frame; margins around gross tumour volume were 5mm in the axial plane and 10mm in the longitudinal direction. Median age was 73.7 years. A pathologic confirmation of NSCLC was obtained in 64.5% of patients. Forty-three patients had stage IA and 19 stage IB disease. The majority of patients did not experience any toxicity; mild skin reactions, fatigue, dyspnea/cough or transient thoracic pain were recorded in approximately 10% of patients. With a median follow-up time of 28 months, 2 patients experienced an isolated local relapse, 4 an isolated nodal relapse and 15 a systemic failure. At 3 years, local control rate was 87.8%, cancer-specific survival 72.5%, overall survival 57.1%, with 8 out of 20 non-cancer related deaths. In multivariate analysis, tumour volume was associated with a better outcome. In our series, SBRT was well tolerated and confirmed its efficacy, with local control and survival rates globally superior to those reported using conventional radiotherapy. A longer follow-up is needed in order to establish a correct comparison with surgical series, and to fully ascertain a potential negative impact of SBRT on comorbidities of such a fragile patients population.

Preoperative Endoscopic Sphincterotomy Versus Laparoendoscopic Rendezvous in Patients With Gallbladder and Bile Duct Stones

Objective:To compare success rate, length of hospital stay, clinical results, and costs of sequential treatment (endoscopic retrograde cholangiopancreatography followed by laparoscopic cholecystectomy) versus the laparoendoscopic Rendezvous in patients with cholecysto-choledocholithiasis. Background:The ideal management of common bile duct (CBD) stones in the era of laparoscopic cholecystectomy (LC) remains controversial. Methods:A total of 91 elective patients with cholelithiasis and CBD stones diagnosed at magnetic resonance cholangiography (MRC) were included in a prospective, randomized trial. The patients were randomized in 2 groups. Group I patients (45 cases) underwent a preoperative endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy (ES) followed by LC in the same hospital admission. Group II patients (46 cases) underwent LC associated with intraoperative ERCP and ES according to the rendezvous technique. Results:The rate of CBD clearance was 80% for Group I and 95.6% for Group II (P = 0.06). The morbidity rate was 8.8% in Group I and 6.5% in Group II (P = not significant). No deaths occurred in either group. Hospital stay was shorter in Group II than in Group I: 4.3 days versus 8.0 days (P < 0.0001). There was a significant reduction in mean total cost for group II patients versus group I patients: &OV0556;2829 versus &OV0556;3834 (P < 0.05). Conclusions:When compared with preoperative ERCP with ES followed by LC, the laparoendoscopic rendezvous technique allows a higher rate of CBD stones clearance, a shorter hospital stay, and a reduction in costs.

Phase II randomized trial comparing vinorelbine versus vinorelbine plus cisplatin in patients with recurrent salivary gland malignancies

Some previous studies have shown that vinorelbine (VNB) is active in recurrent salivary gland tumors.

Stereotactic body radiation therapy for lung metastases

INTRODUCTION Stereotactic body radiation therapy (SBRT) has an emerging role in patients affected with pulmonary metastases. Purpose of this study was to evaluate efficacy and tolerability of SBRT in a cohort of patients treated between 2003 and 2009 at our institution. METHODS A total of 61 patients with oligometastatic lung tumors (single pulmonary nodules in 73.7%) were included in the study. SBRT was performed with a stereotactic body frame and a 3D-conformal technique. Fifty-one patients received 26 Gy in 1 fraction, 22 a dose of 45 Gy in 3 fractions and 3 a dose of 36 Gy in 4 fractions. Primary tumor was lung cancer in 45.7% of patients, colorectal cancer in 21.3% and a variety of other origins in 33%. The primary endpoint was local control, secondary endpoints were survival and toxicity. RESULTS After a median follow-up interval of 20.4 months, local control rates at 2 and 3 years were 89% and 83.5%, overall survival 66.5% and 52.5%, cancer-specific survival 75.4% and 67%, progression-free survival 32.4% and 22.3%. Tumor volume was significantly associated to survival, with highest rates in patients with single small tumors. Median survival time was 42.8 months, while median progression-free survival time was 11.9 months. Toxicity profiles were good, with just one case of grade III toxicity (pneumonitis). CONCLUSION This study shows that SBRT is an effective and safe local treatment option for patients with lung metastases. Definitive results are strictly correlated to clinical selection of patients.

Treatment of malignant neoplasms of the parotid gland

In this study we evaluated the effects of surgical and radiotherapy treatment on local control in 126 patients with malignant tumors of the parotid gland. The most frequently observed malignant tumors were high-grade tumors (68%). Surgical treatment was performed in 81 patients (83.5%). Total conservative parotidectomy was the most frequent procedure (74%), and radiotherapy was performed in 81 patients (83.5%). The global survival rate was approximately 54% at 5 years, whereas disease-free survival was 47% at 5 years. No statistically significant difference in survival rate was found between conservative (52% at 5 years) and radical treatment of the seventh cranial nerve (43% at 5 years). The incidence of recurrent cancer was 25.7% (25 of 97), of which 88% developed during the first 2 years. We report some of the clinical and histologic factors that can influence the prognosis of the disease. (Otolaryngol Head Neck Surg 1999;121:627–32.)

Different IMRT solutions vs. 3D-Conformal Radiotherapy in early stage Hodgkin's lymphoma: dosimetric comparison and clinical considerations

BackgroundRadiotherapy in Hodgkin’s Lymphoma (HL) is currently evolving with new attempts to further reduce radiation volumes to the involved-node concept (Involved Nodes Radiation Therapy, INRT) and with the use of intensity modulated radiotherapy (IMRT). Currently, IMRT can be planned and delivered with several techniques, and its role is not completely clear. We designed a planning study on a typical dataset drawn from clinical routine with the aim of comparing different IMRT solutions in terms of plan quality and treatment delivery efficiency.MethodsA total of 10 young female patients affected with early stage mediastinal HL and treated with 30 Gy INRT after ABVD-based chemotherapy were selected from our database. Five different treatment techniques were compared: 3D-CRT, VMAT (single arc), B-VMAT (“butterfly”, multiple arcs), Helical Tomotherapy (HT) and Tomodirect (TD). Beam energy was 6 MV, and all IMRT planning solutions were optimized by inverse planning with specific dose-volume constraints on OAR (breasts, lungs, thyroid gland, coronary ostia, heart). Dose-Volume Histograms (DVHs) and Conformity Number (CN) were calculated and then compared, both for target and OAR by a statistical analysis (Wilcoxon’s Test).ResultsPTV coverage was reached for all plans (V95% ≥ 95%); highest mean CN were obtained with HT (0.77) and VMAT (0.76). B-VMAT showed intermediate CN mean values (0.67), while the lowest CN were obtained with TD (0.30) and 3D-CRT techniques (0.30). A trend of inverse correlation between higher CN and larger healthy tissues volumes receiving low radiation doses was shown for lungs and breasts. For thyroid gland and heart/coronary ostia, HT, VMAT and B-VMAT techniques allowed a better sparing in terms of both Dmean and volumes receiving intermediate-high doses compared to 3D-CRT and TD.ConclusionsIMRT techniques showed superior target coverage and OAR sparing, with, as an expected consequence, larger volumes of healthy tissues (lungs, breasts) receiving low doses. Among the different IMRT techniques, HT and VMAT showed higher levels of conformation; B-VMAT and HT emerged as the planning solutions able to achieve the most balanced compromise between higher conformation around the target and smaller volumes of OAR exposed to lower doses (typical of 3D-CRT).

Improved survival with perilymphatic interleukin 2 in patients with resectable squamous cell carcinoma of the oral cavity and oropharynx.

The current randomized, multicenter, Phase III trial was conducted to determine whether the disease free interval and overall survival of patients with T2–T4,N0–N3,M0 squamous cell carcinoma (SCC) of the oral cavity or oropharynx could be extended through the combination of surgery (and radiotherapy, if required) with perilymphatic recombinant IL‐2 (rIL‐2).

Dosimetric predictors of radiation-induced lung injury in stereotactic body radiation therapy

Materials and methods. The aim was to retrospectively investigate correlations between potential predictive parameters and the occurrence of radiation-induced lung injury in patients with primary or secondary lung tumours treated with stereotactic body radiation therapy (SBRT). Sixty patients (63 tumours) underwent SBRT, with a dose of 45 Gy in 3 fractions over 5 days or 26 Gy in single fraction. The following parameters were tested for correlation with Radiation Therapy Oncology Group (RTOG) lung toxicity score: planning target volume (PTV), tumour location, primary vs. metastatic tumour, and Mean Lung Dose (in 2 Gy fractions, MLD2). Normal Tissue Complication Probability (NTCP) values were then estimated. Results. The median follow-up time was 30.9 months (range 6.7–56.7). RTOG grade 0–1 toxicity was observed in 54/63 (85.7%) and grade 2–3 in 9/63 (14.3%) cases. Mean values of MLD2 for RTOG grade 0–1 and 2–3 were respectively 11.2 Gy (95% Confidence Interval (CI) 10.1–12.3 Gy) and 20.3 Gy (95% CI 16.6–23.9 Gy). NTCP mean values for RTOG grade 0–1 and 2–3 were respectively 4% (95% CI 2–5.9%) and 37% (95% CI 11.6–62.3%). Univariate analysis, performed with t-Student test, showed a statistically significant difference between MLD2 values in the two groups (t = 5.93 and p ≤ 0.001). Logistic regression analysis showed a good correlation between MLD2 and toxicity scores 2–3 (p = 0.008, odds ratio 1.5). From logistic regression relationship between the observed rates of grade 2–3 and MLD2, a D50=19.8 Gy and a γ50=2.2 were obtained. From the sigmoid-shaped dose-response relationship between NTCP and MLD2, a D50=22.4 Gy and γ50=2.2 were derived. Discussion. MLD2 is strongly associated to the risk of lung injury. Higher NTCP values are associated with a higher risk, but when comparing the expected to the observed toxicity rate, NTCP seems to underestimate the risk.

Distinct Effects of Leukocyte and Cardiac Phosphoinositide 3-Kinase γ Activity in Pressure Overload–Induced Cardiac Failure

Background— Signaling from phosphoinositide 3-kinase &ggr; (PI3K&ggr;) is crucial for leukocyte recruitment and inflammation but also contributes to cardiac maladaptive remodeling. To better understand the translational potential of these findings, this study investigates the role of PI3K&ggr; activity in pressure overload–induced heart failure, addressing the distinct contributions of bone marrow–derived and cardiac cells. Methods and Results— After transverse aortic constriction, mice knock-in for a catalytically inactive PI3K&ggr; (PI3K&ggr; KD) showed reduced fibrosis and normalized cardiac function up to 16 weeks. Accordingly, treatment with a selective PI3K&ggr; inhibitor prevented transverse aortic constriction–induced fibrosis. To define the cell types involved in this protection, bone marrow chimeras, lacking kinase activity in the immune system or the heart, were studied after transverse aortic constriction. Bone marrow–derived cells from PI3K&ggr; KD mice were not recruited to wild-type hearts, thus preventing fibrosis and preserving diastolic function. After prolonged pressure overload, chimeras with PI3K&ggr; KD bone marrow–derived cells showed slower development of left ventricular dilation and higher fractional shortening than controls. Conversely, in the presence of a wild-type immune system, KD hearts displayed bone marrow–derived cell infiltration and fibrosis at early stages but reduced left ventricular dilation and preserved contractile function at later time points. Conclusions— Together, these data demonstrate that, in response to transverse aortic constriction, PI3K&ggr; contributes to maladaptive remodeling at multiple levels by modulating both cardiac and immune cell functions.

Can Ki67 immunostaining predict response to radiotherapy in oral squamous cell carcinoma

AIMS--To determine whether immunohistochemical evaluation of the abatement of proliferating cells after a first course of radiotherapy could predict the final response to treatment in oral squamous cell carcinoma (SCC). METHODS--Frozen sections from 31 cases of histologically confirmed oral SCC were stained with the monoclonal antibody Ki67 at diagnosis and after 10 Gy of radiotherapy. The percentage difference of Ki67 positive cells among the biopsy specimens taken at the beginning and after 10 Gy was correlated with the clinical response obtained at the end of the treatment and its significance determined. RESULTS--The percentage of Ki67 positive cells at diagnosis had no significant correlation with the final therapeutic result of radiotherapy. By contrast, the 32% difference of proliferating cells after 10 Gy of radiotherapy significantly differentiated responders from non-responders (p < 0.05). Furthermore, the abatement of the growth fraction after 10 Gy of radiotherapy was significantly correlated with the complete response (p < 0.01). CONCLUSIONS--These data show that the immunohistochemical evaluation of the abatement of Ki67 positive cells after 10 Gy of radiotherapy provides an independent variable of responsiveness to radiotherapy, allowing a reliable prediction of the final therapeutic result to be made.