Unit of Biostatistics and Clinical Trials

Meldola, Italy

Unit of Biostatistics and Clinical Trials

Meldola, Italy
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Passardi A.,Instituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori | Nanni O.,Unit of Biostatistics and Clinical Trials | Tassinari D.,Per gli Infermi Hospital | Turci D.,S Maria Delle Croci Hospital | And 9 more authors.
Annals of Oncology | Year: 2015

Background: We report the results from a first-line phase III randomized clinical trial on metastatic colorectal cancer (mCRC) aimed at evaluating the effectiveness of adding bevacizumab (B) to standard first-line chemotherapy (CT). Patients and methods: mCRC patients were randomized to receive first-line CT (FOLFIRI or FOLFOX4) plus B (arm A) or CT only (arm B). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (ORR) and safety. Three hundred and fifty patients and 310 events were required to have an 80% statistical power to detect a difference in PFS between the groups. Results: Between November 2007 and March 2012, 376 patients were randomized. About 60% of patients received FOLFOX4 and 40% FOLFIRI. After a median follow-up of 36 months, 343 progressions and 275 deaths had been observed in the overall population. The median PFS was 9.6 [95% confidence interval (CI) 8.2-10.3] and 8.4 (95% CI 7.2-9.0) months for arms A and B, respectively, with a hazard ratio of 0.86 (95% CI 0.70-1.07; P = 0.182). No statistically significant differences in OS or ORR were observed. B-containing regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia. Conclusions: The addition of B to standard first-line CT for mCRC did not provide a benefit in terms of PFS, OS or ORR. Further research is warranted to better identify the target population. © The Author 2015.

PubMed | IT Service, Oncology Pharmacy Laboratory, Bellaria Hospital IRCCS Institute of Neurological science, Guglielmo da Saliceto Hospital and 7 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

To investigate the role of pre-treatment inflammatory indexes (II) as predictors of prognosis and treatment efficacy in patients with metastatic colorectal cancer mCRC randomized onto the prospective multicenter randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial to receive first-line chemotherapy (CT) with or without bevacizumab (Bev).In the overall population, PFS and OS were higher in patients with low SII (p = .015 and .002, respectively), low NLR (p = .0001 and <.0001, respectively) and low PLR (p = .004 and .008, respectively). Patients with low NLR in the CT plus Bev arm had a higher PFS than those treated with CT alone (HR = 0.69, p = .021).Two hundred and eighty-nine patients were considered for this study, 141 receiving CT plus Bev and 148 receiving CT alone. The pre-treatment systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were evaluated to identify a potential correlation with progression-free (PFS) and overall survival (OS) in both the overall population and the 2 treatment arms.Our results indicate that II, in particular NLR, are good prognostic and predictive markers for mCRC patients who are candidates for CT plus Bev.

PubMed | S. Orsola Malpighi University Hospital, University of Ferrara, Instituto Scientifico Romagnolo per lo Studio e Cura dei Tumori IRST IRCCS, Hospital S Maria Nuova and 4 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

Antiblastic drugs have a high number of potential side-effects. Paradoxically, according to the National Network of Pharmacovigilance, the number of reported adverse reactions to these agents is proportionally lower than that registered for non antiblastic drugs. Critical phenomena such as treatment interruptions and significant dose reductions within the first two months of use may be indicators of adverse drug reactions. The aim of the present study was to increase our knowledge of pharmacovigilance to facilitate the actions taken to improve the risk-benefit profile of cancer drugs and, consequently, their safety. This retrospective observational survey was carried out on prescriptions from 1st January 2012 to 31st December 2012.Dose reductions of more than 10% during the first 90 days of therapy were considered as a surrogate indicator of an adverse reaction. Dose interruptions during the first 60 days of therapy were taken into consideration. Of the12,472 patients 1,248 underwent a dose reduction. The drugs that most often required a dose reduction were paclitaxel and oxaliplatin (17.4% and 17.3%, respectively), docetaxel (14.8%), carboplatin (15%), fluorouracil (10.7%) and, among oral medications, capecitabine (6.9%). Of the 1896 patients treated with the same drugs, 9.7% interrupted treatment. Patients required a lower dose reduction than that reported by other authors. Around 15% of cases underwent a 30% dose reduction within three months of starting therapy, indicating a possible adverse reaction. Constant monitoring of dose prescription and continuous training of medical and nursing staff are clearly needed to increase awareness of the importance of reporting adverse events.

Masini C.,Laboratory of Oncology Pharmacy | Nanni O.,Unit of Biostatistics and Clinical Trials | Antaridi S.,Laboratory of Oncology Pharmacy | Gallegati D.,Finance and Management Control | And 4 more authors.
American Journal of Health-System Pharmacy | Year: 2014

Purpose. The quality and economic implications of manual versus automated preparation of antineoplastic drugs were compared. Methods. This four-week study evaluated 10 routinely used antineoplastic drugs (fluorouracil, cyclophosphamide, gemcitabine, trastuzumab, bevacizumab, oxaliplatin, cisplatin, paclitaxel, irinotecan, and etoposide) prepared by manual and automated procedures. The accuracy of the dose of the active ingredient was calculated in terms of percent relative error for the difference between the nominal value indicated on the prescription and the actual value of the drug in the finished product. A comparative economic analysis of the manual and automated preparation procedures was performed by calculating the mean unit cost for each preparation at different production levels. Participating pharmacists and technicians completed a survey rating each preparation method in terms of performance, operator satisfaction, technology, and safety. Results. Of the 2500 i.v. antineoplastic preparations made in the pharmacy during the four-week study period, 681 were analyzed (348 using the automated procedure and 333 manually). Of these, 17 varied by more than 5% of the prescribed dose, and 1 varied by over 10%. Accuracy, calculated in terms of average percent relative error, was the highest and lowest during manual preparation. The preparation time for individual drugs was always higher when prepared using the automated procedure. A lower mean variable unit cost was observed for preparations made using the automated procedure. Questionnaire results revealed that operators preferred the automated procedure over the manual procedure. Conclusion. Both the automated and manual procedures for preparing antineoplastic preparations proved to be accurate and precise. The automated procedure resulted in substantial advantages in terms of quality maintenance standards and risk lowering. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved.

PubMed | D Cotugno Hospital, Unit of Biostatistics and Clinical Trials, University of Cagliari, Biosciences Laboratory and 7 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

We evalueted a systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) with the aim to explored their prognostic value in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. 56 advanced HCC patients receiving sorafenib were available for our analysis. Lymphocyte, neutrophil and platelet were measured before beginning of treatment and after one month. Patient with SII 360 showed lower median PFS (2.6 vs. 3.9 months, P < 0.026) and OS (5.6 vs. 13.9 months, P = 0.027) with respect to patients with SII < 360.NLR 3 had a lower median PFS (2.6 vs. 3.3 months, P < 0.049) but not OS (5.6 vs. 13.9 months, P = 0.062) than those with NLR < 3. After adjusting for clinical covariates SII and NLR remained an independent prognostic factor for OS. The SII and NLR represent potential prognostic indicator in patients with advanced HCC treated with sorafenib.

Maltoni M.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Miccinesi G.,Instituto per Lo Studio e la Prevenzione Oncologica ISPO | Miccinesi G.,Cancer Prevention and Research Institute ISPO | Morino P.,Convento Delle Oblate Hospice | And 7 more authors.
Supportive Care in Cancer | Year: 2012

Purpose Palliative sedation (PS) has been defined as the use of sedative medications to relieve intolerable suffering from refractory symptoms by a reduction in patient consciousness. It is sometimes necessary in end-of-life care when patients present refractory symptoms. We investigated PS for refractory symptoms in different hospice casemixes in order to (1) assess clinical decision-making, (2) monitor the practice of PS, and (3) examine the impact of PS on survival. Methods This observational longitudinal cohort study was conducted over a period of 9 months on 327 patients consecutively admitted to two 11-bed Italian hospices (A and B) with different casemixes in terms ofmedian patient age (hospice A, 66 years vs. hospice B, 73 years; p=0.005), mean duration of hospice stay (hospice A, 13.5 days vs. hospice B, 18.3 days; p=0.005), and death rate (hospice A, 57.2% vs. hospice B, 89.9%; P<0.0001). PS was monitored using the Richmond Agitation-Sedation Scale (RASS). Sedated patients constituted 22% of the total admissions and 31.9% of deceased patients, which did not prove to be significantly different in the two hospices after adjustment for casemix. Results Patient involvement in clinical decision-making about sedation was significantly higher in hospice B (59.3% vs. 24.4%; p=0.007). Family involvement was 100% in both hospices. The maximum level of sedation (RASS, -5) was necessary in only 58.3% of sedated patients. Average duration of sedation was similar in the two hospices (32.2 h [range, 2.5- 253.0]). Overall survival in sedated and nonsedated patients was superimposable, with a trend in favor of sedated patients. Conclusions PS represents a highly reproducible clinical intervention with its own indications, assessment methodologies, procedures, and results. It does not have a detrimental effect on survival. © Springer-Verlag 2012.

PubMed | Marche Polytechnic University, University of Cagliari, Biosciences Laboratory, Morgagni Pierantoni Hospital and 6 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1) vs. 2.5 months (95% CI 1.9-2.6) (p<0.001) and overall survival 14.6 months (95% CI9.7-19.0) vs. 3.9 months (95% CI 3.1-8.7) (p=0.003). Sodium levels were generally higher on day 15 than at baseline (+2.38, p<0.0001) in the group of responders (+4.95, p <0.0001) compared to patients who progressed (PD) (+0.28, p=0.607). In contrast, potassium was lower on day 14 (-0.30, p=0.0008) in the responder group (-0.58, p=0.003) than in those with progressive disease (-0.06, p=0.500). The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatment.

Farolfi A.,Cancer Institute of Romagna IRST | Ridolfi L.,Cancer Institute of Romagna IRST | Guidoboni M.,Cancer Institute of Romagna IRST | Nicoletti S.V.L.,Cancer Institute of Romagna IRST | And 6 more authors.
Melanoma Research | Year: 2012

Patients with metastatic melanoma have a poor prognosis; the results of chemotherapy remain unsatisfactory. Ipilimumab, an anticytotoxic T lymphocyte-associated antigen-4 antibody, has shown promising results in several clinical trials. In this report, advanced melanoma patients receiving ipilimumab were scored according to novel immune-related response criteria (irRC) in an attempt to capture additional response patterns and to avoid premature treatment cessation. Thirty-six heavily pretreated metastatic melanoma patients recieved ipilimumab within five international clinical trials at our Institution from May 2006 to August 2008. Disease progression was defined as an increase in tumor burden by at least 25% compared with the nadir, irrespective of any initial increase in baseline lesions or the appearance of new lesions. We report unusually long-lasting responses in patients treated with ipilimumab 10 mg/kg. An overall response was observed in six out of 30 patients (20%), a complete response in three (10%), and disease control in 11 (37%), which seemed to be of a long duration (median of 16 months; complete response 36+, 34+, and 41+ months). All irRC patterns seemed to be strongly associated with an improvement in overall survival. Interestingly, we found a correlation between the presence of a grade 3/4 immune-related adverse event and responses, time to progression, and overall survival. Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, supporting the need for further irRC validation. Copyright © Lippincott Williams & Wilkins.

Farolfi A.,Instituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST IRCCS | Melegari E.,Instituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST IRCCS | Aquilina M.,Cardiology Unit | Scarpi E.,Unit of Biostatistics and Clinical Trials | And 12 more authors.
Heart | Year: 2013

Objective: Although adjuvant trastuzumab improves survival in patients with HER2-positive early breast cancer, there is growing concern about the long-term effect of trastuzumab-induced cardiotoxicity (TIC). We retrospectively assessed the incidence of TIC and heart failure (HF) to identify possible risk and protective factors. Design: Retrospective study. Setting: Institute for Cancer Research and Treatment, Medical: Oncology Department. Patients: Consecutive patients who started adjuvant trastuzumab between 2007 and 2010. Main outcome: Measures TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥15 points from baseline or a LVEF<50%. Logistic regression was used to estimate OR and their 95% CI in order to evaluate the risk of TIC, considering potential cardiac risk factors (hypertension, hypercholesterolaemia, diabetes mellitus, smoke, cardiac ischaemia and previous chest radiotherapy) and protective factors (β-blockers, ACE inhibitors and/or angiotensin receptor blockers). Results: Among 179 patients, 78 cases of TIC (44%, 95% CI 37% to 51%) and four cases of HF (2%, 95% CI 0% to 4%) were reported. 14 patients stopped trastuzumab as a result of TIC. None of the cardiac risk factors or concomitant cardiovascular medications altered the risk of TIC. A previous cumulative dose ≥240 mg/m2 of doxorubicin or >500 mg/m2 of epirubicin increased the risk of TIC compared with lower doses (OR 3.07;95% CI 1.29 to 7.27, p=0.0011). Conclusions: TIC is a frequent, albeit generally mild, adverse event in clinical practice. Further studies are warranted to better define the risk of and protective factors for TIC.

e14161 Background: The commercialization of two monoclonal antibodies, bevacizumab (Bev) and cetuximab (Cetux) raises important questions about their use in the first- and second-line treatment of metastatic colorectal cancer. At present, their role in clinical practice is not well defined, especially in terms of timing of administration and possible side-effects compared to chemotherapy (CT) alone.Patients eligible for first-line treatment will be randomized to either treatment arm A: CT (FOLFOX or FOLFIRI at the physicians discretion) + Bev or arm B: CT alone. The primary objective of this part of the study is to compare progression-free survival (PFS) in treatment arms. Upon progression, patients from arm A with Kras wild-type tumors will be randomized to arm C (the other CT schedule alone) or arm D (the other CT schedule + Cetux). Arm B patients with wild-type Kras will be randomized to arm E (the other CT + Bev) or arm F (the other CT+ Bev + Cetux). The superiority hypothesis regarding the use of Bev in first-line therapy requires 310 events (progressions) in a total of 350 patients to detect an absolute increase in PFS of 3 months, corresponding to a 27% relative reduction in the progression rate, with a 2-sided 5% significance level and an 80% power. It is assumed that about 75 patients will be included in each of the second-line studies. PFS as primary objective is an amendment currently under evaluation of the Ethical Committee. The objective response rates, OS and safety are secondary endpoints. The identification and evaluation of the role of tumor markers in predicting treatment response is one of the sub studies.This independent study will be funded by the Italian Ministry of Health. At the end of December 2010, 24 centers had received Ethics Committee approval, and 23 are currently recruiting patients. To date a total of 267 patients have been randomized onto the first-line study.We plan to close recruitment in December 2011 and perform the final analysis in September 2012.

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