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Petrelli F.,Azienda Ospedaliera Treviglio Caravaggio | Borgonovo K.,Azienda Ospedaliera Treviglio Caravaggio | Cabiddu M.,Azienda Ospedaliera Treviglio Caravaggio | Ghilardi M.,Azienda Ospedaliera Treviglio Caravaggio | Barni S.,Azienda Ospedaliera Treviglio Caravaggio
International Journal of Colorectal Disease | Year: 2011

Background Anti-epidermal growth factor receptor monoclonal antibodies (panitumumab [P] and cetuximab [C]) are approved and effective only in KRAS wild-type patients with advanced colorectal cancer. The purpose of our meta-analysis is to evaluate the real effects of C and P in KRAS wild-type patients treated in randomized trials. Patients and methods Eligible studies included prospective, randomized, and controlled trials in which either C or P had been added to standard antineoplastic therapy or best supportive care and data for KRAS wild-type patients only had been calculated. Six thousand three hundred ninety-five patients' tumor samples have been analyzed (total wild-type n=3,254; experimental arm n=1,608; control arm n=1,646). Relative risks (RRs) with 95% confidence intervals (CIs) for response rate were calculated, as well as hazard ratios (HRs) for progression-free survival (PFS) and overall survival. Results The overall RR of response rate is 1.69 (p =0.003) in all trials. The overall HRs for PFS and survival are 0.65 (p = 0.0006) and 0.84 (p=0.03), respectively, and both are significant. The HRs for PFS and survival in C trials are 0.64 and 0.79, respectively, and 0.65 and 0.87, respectively, in P trials, although only the results achieved in P trials are significant (p=0.0007 and p=0.03). Both response rate (RR=10.94) and PFS (HR=0.51) have increased more in pretreated patients than in first-line trials. Conclusion The addition of anti-EGFR monoclonal antibodies to standard anticancer therapy in KRAS wild-type colorectal cancer showed an overall significantly increased risk of objective response rate and increased progressionfree and overall survival. Only the results achieved in P randomized trials are significant, and the strongest results have been achieved in pretreated patients. © 2011 Springer-Verlag.


Petrelli F.,Azienda Ospedaliera Treviglio Caravaggio | Borgonovo K.,Azienda Ospedaliera Treviglio Caravaggio | Cabiddu M.,Azienda Ospedaliera Treviglio Caravaggio | Lonati V.,Azienda Ospedaliera Treviglio Caravaggio | Barni S.,Azienda Ospedaliera Treviglio Caravaggio
Breast Cancer Research and Treatment | Year: 2012

The contribution of adjuvant taxanes (T) in cardiovascular toxicity, leukemic risk, and non-cancerrelated deaths is unknown when they are added to anthracycline (A)-based chemotherapy for breast cancer. We performed a meta-analysis of published randomized controlled trials (RCTs) to determine the risk of cardiovascular toxicity, leukemia, neurotoxicity, and non-breast cancerrelated mortality associated with T added to adjuvant A in breast cancer. PubMed was searched to identify relevant studies. Eligible studies included prospective RCTs in which approved T in combination with A (A + T) were compared with A alone as adjuvant chemotherapy for breast cancer. Summary incidence rates, relative risks (RRs), and 95 % confidence intervals were calculated by means of fixed-or random-effects models. A total of 27,039 patients from 15 RCTs were included. Compared with A alone, A + T was associated with a statistically similar risk of toxicity. Compared with control arms, A + T schedules with less cumulative dose of anthracyclines than control arms were associated with lower severe cardiotoxicity (RR = 0.41, [95% CI 0.26-0.66], P = 0.0002), venous thromboembolic events (RR 0.45, [95% CI 0.26-0.79], P = 0.006), and leukemic risk (RR 0.39; [95%CI 0.18-0.87] P = 0.02), but with an increased risk of non-breast cancer-related mortality (RR = 1.79, [95% CI 1.06-3.04] P = 0.03). In particular, this risk of death is greater when>3 cycles of A precede T in sequential schedules (RR 2.24, [1.2-4.21] P = 0.01). This meta-analysis suggests that A + T-based adjuvant chemotherapy is as toxic asAalonewith no significant difference in non-breast cancer-related mortality. However, sequential A + T schedules are associated with less toxicity, but a significant increase in non-breast cancer-related mortality compared with control arms with a greater dose of A. © Springer Science+Business Media, LLC. 2012.


Petrelli F.,Azienda Ospedaliera Treviglio Caravaggio | Borgonovo K.,Azienda Ospedaliera Treviglio Caravaggio | Cabiddu M.,Azienda Ospedaliera Treviglio Caravaggio | Barni S.,Azienda Ospedaliera Treviglio Caravaggio
Clinical Lung Cancer | Year: 2012

Advanced nonsmall-cell lung cancer (NSCLC) harboring activating mutations of epidermal growth factor receptor (EGFR) are particularly sensitive to tyrosine kinase inhibitors (TKIs), namely erlotinib and gefitinib. The purpose of this meta-analysis was to evaluate the benefit of EGFR TKIs in EGFR-mutated NSCLCs. Eligible studies included published randomized controlled trials in which erlotinib or gefitinib (alone or with chemotherapy) were compared with standard therapy in 1260 patients with EGFR-mutated NSCLCs who were included in 13 trials. The mutational status was obtained through a retrospective or prospective analysis. Relative risk (RR) was calculated for response rate, and hazard ratios (HRs) were calculated for progression-free and overall survival. EGFR TKIs increase the chance of obtaining an objective response almost 2-fold when compared with chemotherapy (RR, 2.06; 2p <.00001). The response rate was 70% vs. 33.2% in first-line trials. In 3 second-line trials, response rates were 47.4% vs. 28.5%, with a benefit similar to first-line trials (RR, 1.79; 2p =.04). EGFR TKIs reduced the hazard of progression by 70% in all trials (HR, 0.30; 2p <.00001) and by 65% in first-line trials only (HR, 0.35; 2p <.00001). Overall, however, they do not improve survival (HR, 0.96; 2p =.71). NSCLCs harboring EGFR mutations derive greater benefit from erlotinib or gefitinib than from chemotherapy. All patients affected by NSCLC with an EGFR-positive mutation test result must be offered the opportunity to be treated with an EGFR TKI upfront or during the natural course of the disease if not previously exposed. © 2012 Elsevier Inc. All rights reserved.


Petrelli F.,Azienda Ospedaliera Treviglio Caravaggio | Cabiddu M.,Azienda Ospedaliera Treviglio Caravaggio | Barni S.,Azienda Ospedaliera Treviglio Caravaggio
Medical Oncology | Year: 2012

The aim of this pooled-analysis is to evaluate the benefit of capecitabine (C) versus standard intravenous 5-Fluorouracil (5-FU) as monochemotherapy or combination therapy in advanced colorectal cancer (CRC) in terms of safety and efficacy. Eligible patients have been randomized to receive either C-based or 5-FU-based chemotherapy for the treatment of advanced CRC. Relative risks (RRs) with 95% confidence intervals (CIs) of selected side effects (diarrhea, nausea, vomiting, stomatitis, hand and foot syndrome, neutropoenia, febrile neutropoenia, and cardio toxicity) and overall response rate (ORR) were calculated and hazard ratios (HRs) of progression-free survival (PFS) and overall survival were obtained, respectively, from published data. The RRs of stomatitis and neutropoenia are 0.39 and 0.40, respectively with C (P<0.00001). In particular high-grade mucositis and neutropoenia, they are reduced by 69 and 74%, respectively (RR: 0.31 and 0.26). Diarrhea, nausea, vomiting, febrile neutropoenia, and cardio toxicity with C are not worse than with 5-FU. The RR of hand and foot syndrome with C compared to 5-FU is 3.45, (P<0.00001). Response rate, PFS, and OS are equivalent in both C- and 5-FUbased regimens. The use of C instead of 5-FU in advanced colorectal cancer regimens results in significantly less toxicity in terms of stomatitis and neutroponenia. Only hand and foot syndrome is worse with C than with 5-FU. Activity and efficacy are similar. Capecitabine could be therefore considered standard of care in advanced CRC. © Springer Science+Business Media, LLC 2011.


Petrelli F.,Medical Oncology Unit | Borgonovo K.,Azienda Ospedaliera Treviglio Caravaggio | Cabiddu M.,Azienda Ospedaliera Treviglio Caravaggio | Ghilardi M.,Azienda Ospedaliera Treviglio Caravaggio | Barni S.,Azienda Ospedaliera Treviglio Caravaggio
Expert Opinion on Drug Safety | Year: 2012

Introduction: The typical class side effect of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (panitumumab and cetuximab) is a cutaneous maculopapular rash, although hypomagnesemia is also described to be a frequent adverse event. The purpose of our meta-analysis is to evaluate the frequency and the relative risk of hypomagnesemia in patients treated with cetuximab or panitumumab in randomized trials. Area covered: Eligible studies included prospective randomized Phase III controlled trials in which cetuximab or panitumumab were compared with standard anti-neoplastic therapy or best supportive care. Summary incidence rates and relative risks with 95% confidence intervals were calculated. Expert opinion: The overall incidence of hypomagnesemia was 17% among the patients who received the treatment, whose risk of developing hypomagnesemia turned out to be significantly increased compared with the patients treated with control medication, with an overall relative risk of 5.83 (p < 0.00001), where 3.87 refers to cetuximab and 12.55 to panitumumab. The addition of anti-EGFR monoclonal antibodies to standard anticancer therapy showed a significantly increased risk of hypomagnesemia compared with controls. The risk seems to be even higher for panitumumab, probably correlated with the increased risk of other adverse events (e.g., diarrhea and dehydration). Hypomagnesemia does not seem to be linked with any serious complications. © 2012 Informa UK, Ltd.


Petrelli F.,Azienda Ospedaliera Treviglio Caravaggio | Barni S.,Azienda Ospedaliera Treviglio Caravaggio
Medical Oncology | Year: 2012

Bevacizumab is approved for use as first-line therapy in advanced breast cancer according to pivotal ECOG 2,100 trial. Recently, Food and Drug Administration (FDA) voted unanimously against this licensed indication from the product's labeling. This is because 2 other trials have been conducted (AVADO and RIBBON-1) and both have shown a statistically significant improvement in progression-free survival, although of a much smaller magnitude than was seen in E2100 study. After metaanalysing 2-s-line randomized bevacizumab trials that addressed a little bit different populations (a pure secondline population in RIBBON2 and an heavily pretreated [1-2 previous lines] population in Miller trial), we have discovered that overall response rate (relative risk 1.63; 95% CI 1.02-2.62; P = 0.04) and progression-free survival (hazard ratio 0.85; 95% CI 0.73-0.98; P = 0.03) were significantly increased with the addition of bevacizumab to chemotherapy. Despite both trials, the results are not significant in terms of duration of responses; however, bevacizumab appears not to increase the toxicity of chemotherapy (in particular febrile neutropenia). In conclusion, bevacizumab label in breast cancer could be reconsidered at least for second-line setting where a standard option does not exist, and a real difference in OS is unproven and unnecessary with any regimen in randomized trials. © 2011 Springer Science+Business Media, LLC.


Petrelli F.,Azienda Ospedaliera Treviglio Caravaggio | Barni S.,Azienda Ospedaliera Treviglio Caravaggio
Medical Oncology | Year: 2012

Adjuvant trastuzumab (T) significantly reduces the risk of progression and death in HER-2 positive highrisk early breast cancer. The differential benefit of T, administered either sequential or concomitant, has been calculated with 2 comparative meta-analyses of randomized trials. We have meta-analyzed sequential and concomitant arms of 6 T adjuvant trials separately and then calculated the pooled hazard ratios (HRs) for disease-free survival (DFS) and overall survival (OS) in both metaanalyses. Primary cardiac event rates have also been metaanalyzed. In the concomitant T meta-analysis, HRs for DFS and OS were 0.62 and 0.68, respectively (P < 0.0001 and <0.00001 for both endpoints). Conversely, in the sequential T meta-analysis, HRs for DFS and OS were, respectively, 0.74 and 0.87, where P is, however, significant only in the first comparison (P < 0.00001 and P = 0.09). Relative risks (RRs) for major cardiac events (severe cardiac hearth failure or death) are 2.44 (P = 0.07) in the concomitant T meta-analysis and 8.35 (P < 0.0001) in the sequential T meta-analysis. Concomitant adjuvant T therapy seems to give a significant and greater benefit than sequential administration in both DFS and OS, and the number of cases of severe cardiotoxicity does not seem to be higher in concomitant administration than in the sequential one. © Springer Science+Business Media, LLC 2011.


Petrelli F.,Azienda Ospedaliera Treviglio Caravaggio | Cabiddu M.,Azienda Ospedaliera Treviglio Caravaggio | Carpo M.,Neurology Unit | Ghilardi M.,Azienda Ospedaliera Treviglio Caravaggio | Barni S.,Azienda Ospedaliera Treviglio Caravaggio
Nature Reviews Urology | Year: 2010

Background. A 57-year-old woman presented with metastatic renal cell carcinoma (RCC). She was enrolled in a clinical study, in which she received two cycles of neoadjuvant sunitinib therapy followed by cytoreductive nephrectomy. Her primary tumor and rib metastasis showed a good response to neoadjuvant therapy; however, after surgery, the patient developed neurologic symptoms, including flaccid paraparesis with paresthesia and hypoesthesia. MRI of the brain and spine revealed a leptomeningeal lesion at the T12-L1 space, which was presumed to have progressed during the 3-week treatment-free perioperative period. The patient underwent radiation therapy for the intramedullary lesion 1 month later, and sunitinib therapy was subsequently reinstated. After 6 months, her extracranial lesions remained stable and the intramedullary lesion was undetectable on MRI. Investigations. CT of the chest and abdomen, bone scan, kidney and liver function tests, measurement of serum levels of calcium, electrolytes and lactate dehydrogenase, CBC, MRI of the brain and spine. Diagnosis. Progression of a central nervous system metastasis linked to the interruption of neoadjuvant sunitinib therapy. Management. Neoadjuvant sunitinib therapy followed by cytoreductive nephrectomy for the primary RCC; radiation therapy for the intramedullary lesion, followed by reinstatement of sunitinib therapy owing to a good clinical response observed in the extracranial lesions. © 2010 Macmillan Publishers Limited. All rights reserved.


Petrelli F.,Azienda Ospedaliera Treviglio Caravaggio | Borgonovo K.,Azienda Ospedaliera Treviglio Caravaggio | Cabiddu M.,Azienda Ospedaliera Treviglio Caravaggio | Barni S.,Azienda Ospedaliera Treviglio Caravaggio
Anti-Cancer Drugs | Year: 2011

Three randomized trials (SATURN, ATLAS and IFCT-GFPC 0502) have demonstrated that the oral antiepidermal growth factor receptor tyrosine kinase inhibitor erlotinib can improve progression-free survival (PFS) and overall survival (OS), as maintenance therapy after first-line chemotherapy in advanced non-small cell lung cancer. We pooled the results of these three trials by performing a meta-analysis of hazard ratios (HRs) and the 95% confidence intervals (CIs) for the PFS and the OS for maintenance erlotinib versus observation, standard therapy or placebo. The benefits in the predefined subgroups of patients [according to histology, sex, performance status (PS), and smoking status] were assessed. The OS was superior in the 963 patients treated with erlotinib than in the 979 nontreated patients [HR=0.87 (P=0.003), corresponding to a 13% reduction in the risk of death. The pooled HR for the PFS is 0.76 (P<0.00001), corresponding to a 24% lower risk of being progression free]. All the patients in the subgroup analysis experienced a benefit from erlotinib and, in particular, never-smoking women with nonsquamous histology with a PS of 0. Both responders and those with stable disease obtain PFS benefit. The addition of maintenance erlotinib significantly improves PFS and OS in patients with advanced non-small cell lung cancer who had not progressed after four cycles of first-line chemotherapy. The benefit does not seem to be limited to a particular subgroup, although it is more pronounced in never-smoking women patients with nonsquamous carriers with a PS of 0. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Petrelli F.,Azienda Ospedaliera Treviglio Caravaggio | Coinu A.,Azienda Ospedaliera Treviglio Caravaggio | Borgonovo K.,Azienda Ospedaliera Treviglio Caravaggio | Cabiddu M.,Azienda Ospedaliera Treviglio Caravaggio | And 4 more authors.
Pancreas | Year: 2015

Objective The use of neoadjuvant chemotherapy can enable surgical resection of borderline resectable or unresectable pancreatic cancer (PC). The aim of this study was to evaluate the effectiveness of the multiagent 5-fluorouracil + oxaliplatin + irinotecan + leucovorin (FOLFIRINOX) regimen as a neoadjuvant treatment for PC. Methods Studies in which FOLFIRINOX with or without radiotherapy was given before surgery to patients with borderline resectable or unresectable PC were analyzed using a meta-analytical approach. The primary outcomes were resection rate and radical (R0) resection rate. Data were expressed as weighted pooled proportions with 95% confidence intervals (CIs). Results Thirteen studies, with a total of 253 patients, were included in this meta-analysis. After undergoing the treatment, 43% (95% CI, 32.8-53.8) of patients were resected and 39.4% (95% CI, 32.4-46.9) underwent R0 resection (85% of surgical specimens). In particular, among borderline resectable PCs, R0 resection was possible in 63.5% (95% CI, 49%-76%) of the cases. The rate of R0 resection in unresectable PCs was 22.5% (95% CI, 13.3-35.4). Conclusions This meta-analysis shows that down-staging after neoadjuvant FOLFIRINOX-based therapy is noticeable in patients with borderline resectable/unresectable PC, with a total R0 resection rate of 40%. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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