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Aviano, Italy

Lorusso D.,Italian National Cancer Institute | Scambia G.,Catholic University of Rome | Pignata S.,Urologic | Sorio R.,CRO Aviano | And 14 more authors.
Annals of Oncology | Year: 2016

Background: Current evidence suggest that trabectedin is particularly effective in cells lacking functional homologous recombination repair mechanisms. A prospective phase II trial was designed to evaluate the activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype. Patients and methods: A total of 100 patients with recurrent BRCA-mutated ovarian cancer and/or BRCAness phenotype (≥ 2 previous responses to platinum) were treated with trabectedin 1.3 mg/mq i.v. q 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms [single-nucleotide polymorphisms (SNPs)] involved in DNA gene repair was analyzed. Results: Ninety-four were evaluable for response; in the whole population, 4 complete and 33 partial responses were registered for an overall response rate (ORR) of 39.4. In the platinum-resistant (PR) and -sensitive (PS) population, an ORR of 31.2% and 47.8%, and an overall clinical benefit of 54.2% and 73.9%, respectively, were registered. In the whole series, the median progression-free survival (PFS) was 18 weeks and the median overall survival (OS) was 72 weeks; PS patients showed a more favorable PFS and OS compared with PR patients. BRCA gene mutational status was available in 69 patients. There was no difference in ORR, PFS and OS according to BRCA 1-2 status nor any association between SNPs of genes involved in DNA repair and NER machinery and response to trabectedin was reported. Conclusions: Our data prospectively confirmed that the signature of 'repeated platinum sensitivity' identifies patients highly responsive to trabectedin. In this setting, the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum. EudraCT Number: 2011-001298-17. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Locatelli S.L.,Humanitas Cancer Center | Locatelli S.L.,University of Milan | Cleris L.,Fondazione Istituto Nazionale Tumori | Stirparo G.G.,Humanitas Cancer Center | And 9 more authors.
Leukemia | Year: 2014

Relapsed/refractory Hodgkin's lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70-80%) and a marked increase in cell death (up to 96%) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50% reduction in tumor burden (P<0.0001), a 5- to 15-fold increase in BIM expression (P≤0.0001) and a fourfold increase in tumor necrosis in Givinostat/Sorafenib-treated animals compared with mice that received single agents. These results provide a rationale for exploring Givinostat/Sorafenib combination in relapsed/refractory HL. © 2014 Macmillan Publishers Limited.


Lee C.K.,University of Sydney | Gurney H.,University of Sydney | Brown C.,University of Sydney | Sorio R.,CRO Aviano | And 12 more authors.
British Journal of Cancer | Year: 2011

Background: We assess the prognostic value of chemotherapy-induced leukopenia and sensory neuropathy in the CALYPSO trial patients treated with carboplatin-paclitaxel (CP) or carboplatin-liposomal doxorubicin (CPLD).Methods:We performed a landmark analysis at first month after randomisation to correlate leukopenia (nadir white blood cell 4.0 × 10 9 per litre or severe infection) during cycle 1 of chemotherapy with progression-free survival (PFS). Using time-dependent proportional-hazards models, we also investigated the association between neuropathy and PFS.Results:Of 608 patients with nadir blood and did not receive growth factors, 72% (CP70%, CPLD73%) had leukopenia. Leukopenia was prognostic for PFS in those receiving CP (adjusted hazard ratio (aHR) 0.66, P0.01). Carboplatin-liposomal doxorubicin was more effective than CP in patients without leukopenia (aHR 0.51, P0.001), but not those experiencing leukopenia (aHR 0.93, P0.54; interaction P0.008).Of 949 patients, 32% (CP62%, CPLD28%) reported neuropathy during landmark. Neuropathy was prognostic for PFS in the CP group only (aHR 0.77, P0.02). Carboplatin-liposomal doxorubicin appeared to be more effective than CP among patients without neuropathy (aHR 0.70, P0.0001), but not those with neuropathy (aHR 0.96, P0.81; interaction P0.15). Conclusion: First-cycle leukopenia and neuropathy were prognostic for patients treated with CP. Efficacy of CP treatment was similar to CPLD in patients who developed leukopenia. These findings support further research to understand the mechanisms of treatment-related toxicity. © 2011 Cancer Research UK All rights reserved.


Avanzo M.,CRO Aviano | Trovo M.,CRO Aviano | Stancanello J.,General Electric | Jena R.,University of Cambridge | And 4 more authors.
Physica Medica | Year: 2015

Purpose: To reduce the fraction number in Partial Breast Irradiation (PBI) with initial prescription of 40 Gy in 10 fractions using radiobiological models with specific focus on risk of moderate/severe radiation-induced fibrosis (RIF) and report clinical results. Methods and materials: 68 patients (patient group A) were treated with 40 Gy in 10 fractions delivered by field-in-field, forward-planned IMRT. Isotoxic regimens with decreasing number of fractions were calculated using Biological Effective Dose (BED) to the breast. Risk for RIF in hypofractionated treatment was predicted by calculating NTCP from DVHs of group A rescaled to fractions and dose of novel regimens. Moderate/severe RIF was prospectively scored during follow-up. Various NTCP models, with and without incomplete repair correction, were assessed from difference to observed incidence of RIF. In order to verify the value for α/β of 3 Gy assumed for breast, we fitted α/β to observed incidences of moderate/severe RIF. Results: Treatments with 35 Gy/7f and 28 Gy/4f were selected for the fraction reduction protocol. 75 patients (group B) were treated in 35 Gy/7f. Incidence of moderate/severe RIF was 5.9% in group A, 5.3% in group B. The NTCP model with correction for incomplete repair had lowest difference from observed RIF. The α/β obtained from fitting was 2.8 (95%CIs 1.1-10.7) Gy. Conclusions: The hypofractionated regimen was well tolerated. The model for NTCP corrected for incomplete repair was the most accurate and an assumed α/β value of 3 Gy is consistent with our patient data. The hypofractionation protocol is continuing with patients treated with 28 Gy/4f. © 2015 Associazione Italiana di Fisica Medica.

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