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Giacomo Allegrini,
Teresa Di Desidero,
Maria Teresa Barletta,
Anna Fioravanti,
Paola Orlandi,
Bastianina Canu,
Silvio Chericoni,
Fotios Loupakis,
Antonello Di Paolo,
Gianluca Masi, Andrea Fontana,
Sara Lucchesi,
Giada Arrighi,
Mario Giusiani,
Andrea Ciarlo,
Giovanni Brandi,
Romano Danesi,
Robert S Kerbel,
Alfredo Falcone,
Guido Bocci
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ABSTRACT: To evaluate UFT and cyclophosphamide (CTX) based metronomic chemotherapy plus celecoxib (CXB) for the treatment of patients with heavily pre-treated advanced gastrointestinal malignancies.
Thirty-eight patients received 500 mg/mq(2) CTX i.v bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 100 mg/twice a day UFT p.o. and 200 mg/twice a day CXB p.o. Tegafur, 5-FU, 5-FUH(2), GHB and uracil pharmacokinetics were assessed. Plasma vascular endothelial growth factor (VEGF), soluble VE-cadherin (sVE-C) and thrombospondin-1 (TSP-1) levels were detected by ELISA and real-time PCR of CD133 gene expression on peripheral blood mononuclear cell was also performed.
Seventeen patients (45%) obtained stable disease (SD) with a median duration of 5.8 ms (range, 4.2-7.4). Median progression free survival (PFS) and overall survival (OS) were 2.7 ms (95% CI, 1.6-3.9 ms) and 7.1 ms (95% CI, 4.3-9.9 ms), respectively. No toxicities of grade >1 were observed. Pharmacokinetics of 27 patients (13/14, SD/progressive disease, PD) after the first treatment of UFT revealed that 5-FU AUC and C(max) values greater than 1.313 h × μg/ml and 0.501 μg/ml, respectively, were statistically correlated with stabilization of disease and prolonged PFS/OS. VEGF and sVE-C plasma levels were greater in the PD group when compared to SD group. CD133 expression increased only in the PD patients.
Metronomic UFT and CTX with CXB in heavily pre-treated gastrointestinal patients were well tolerated and associated with interesting activity. Potential predictive pharmacokinetic parameters and pharmacodynamic biomarkers have been found.
Angiogenesis 03/2012; 15(2):275-86. · 6.06 Impact Factor
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ABSTRACT: Prostate cancer is a common disease in the elderly, and the number of older prostate cancer patients will probably increase with both the aging of the population and the increased rate of screening. In elderly patients with several co-morbidities, cancer management can be complex, and the risk of administering toxic therapy in this setting should be carefully evaluated. Metronomic chemotherapy, i.e. low-dose, long-term, frequently administered chemotherapy, has been shown to have a significant stabilizing effect on cancer and a positive impact on the quality of life of patients, including those with prostate cancer. Given the low toxicity profile of metronomic chemotherapy, elderly patients or patients with co-morbidities may be candidates for a first-line or second-line oral metronomic approach when standard chemotherapies are contraindicated or not acceptable to the patient. Moreover, the possibility of patients being able to spend more time at home is an important component of a palliative treatment such as metronomic chemotherapy. Unfortunately, and despite these considerations, very few data are available on the activity and safety of metronomic chemotherapy in elderly patients. However, retrospective analyses conducted in a small cohort of patients have been published and, notwithstanding their limitations, indicate that novel metronomic schedules are well tolerated, safe and show potentially interesting activity in elderly, 'unfit' (poor performance status) patients with metastatic prostate cancer. Therefore, evaluation of metronomic chemotherapy strategies in prospective, randomized, phase II/III clinical studies of elderly patients with metastatic prostate cancer appears to be warranted.
Drugs & Aging 09/2010; 27(9):689-96. · 2.67 Impact Factor
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Andrea Fontana,
Guido Bocci,
Luca Galli,
Manolo D'Arcangelo,
Lisa Derosa,
Anna Fioravanti,
Paola Orlandi,
Maria Teresa Barletta,
Lorenza Landi,
Simona Bursi,
Gabriele Minuti,
Eleonora Bona,
Ilaria Grazzini,
Romano Danesi,
Alfredo Falcone
Journal of the American Geriatrics Society 05/2010; 58(5):986-8. · 3.74 Impact Factor
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Andrea Fontana,
Luca Galli,
Anna Fioravanti,
Paola Orlandi,
Costanza Galli,
Lorenza Landi,
Simona Bursi,
Giacomo Allegrini,
Eloise Fontana,
Roberta Di Marsico,
Andrea Antonuzzo,
Manolo D'Arcangelo,
Romano Danesi,
Mario Del Tacca,
Alfredo Falcone,
Guido Bocci
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ABSTRACT: The aims of the present study were to evaluate the clinical activity and the pharmacodynamic profile of the novel schedule of a single i.v. standard dose of cyclophosphamide (CTX) immediately followed by an oral metronomic CTX regimen with celecoxib (CXB) and dexamethasone (DEX) in advanced hormone-refractory prostate cancer patients.
Twenty-eight patients (68% docetaxel-resistant) received 500 mg/m2 CTX i.v. bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 200 mg/twice a day CXB p.o. and 1 mg/day DEX p.o. until disease progression. Plasma vascular endothelial growth factor (VEGF) and thrombospondin-1 were detected by ELISA, and real-time reverse transcription-PCR of VEGF and thrombospondin-1 gene expression on peripheral blood mononuclear cell and of VE-cadherin (VE-C) in blood samples was done.
A confirmed prostate-specific antigen decrease of > or =50% from baseline was observed in 9 of 28 patients (32%). Median progression-free survival and overall survival were 3 months (95% confidence interval, 2.2-4.2 months) and 21 months (95% confidence interval, 12.4-29.4 months), respectively. Toxicity was mild and no grade 3 to 4 toxicities occurred. A significant relationship was found between plasma VEGF and prostate-specific antigen values (r = 0.4223; P < 0.001). VEGF levels significantly increased in nonresponders, whereas the responder patients maintained significantly lower levels of VE-C gene expression after the beginning of the treatment if compared with nonresponder ones.
Metronomic CTX plus CXB and DEX showed favorable toxicity and activity profile in patients. VE-C gene expression and VEGF levels represent potentially useful pharmacodynamic markers for the clinical response.
Clinical Cancer Research 09/2009; 15(15):4954-62. · 7.74 Impact Factor
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Francesco Graziano,
Annamaria Ruzzo,
Fotios Loupakis,
Emanuele Canestrari,
Daniele Santini,
Vincenzo Catalano,
Renato Bisonni,
Umberto Torresi,
Irene Floriani,
Gaia Schiavon,
Francesca Andreoni,
Paolo Maltese,
Eliana Rulli,
Bostjan Humar,
Alfredo Falcone,
Lucio Giustini,
Giuseppe Tonini, Andrea Fontana,
Gianluca Masi,
Mauro Magnani
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ABSTRACT: Regulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy.
Patients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)(n) dinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response.
In 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (chi(2) test = 12.7; P = .001) and treatment response (chi(2) test = 9.45; P = .008) than EGFR intron-1 L/L carriers.
Although additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.
Journal of Clinical Oncology 03/2008; 26(9):1427-34. · 18.37 Impact Factor
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ABSTRACT: In recent years, the treatment of metastatic colorectal cancer has improved because of the availability of 3 active cytotoxic drugs, 2 monoclonal antibodies, and the expanded use of surgery on metastases in selected patients, leading to a median overall survival of almost 2 years. Chemotherapy remains the primary option for these patients, and the development of first-line chemotherapy regimens associated with higher activity and improved efficacy is still a major topic of interest. This article provides an overview of the development of a first-line treatment combination of irinotecan and oxaliplatin plus 5-fluorouracil (5-FU; FOLFOXIRI) or oral fluoropyrimidines in patients with metastatic colorectal cancer, evaluating the feasibility and the activity of these regimens in phase I/II studies and the results of a recent phase III study that demonstrates that FOLFOXIRI significantly increases response rate, radical surgical resection of metastases, progression-free survival, and overall survival compared with an infusional 5-FU-containing doublet such as FOLFIRI (5-FU/leucovorin/irinotecan).
Clinical Colorectal Cancer 02/2008; 7(1):7-14. · 1.68 Impact Factor
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Journal of Clinical Oncology 11/2006; 24(28):4668-9; author reply 4669. · 18.37 Impact Factor
