Search

Many active cytotoxic drugs, given according to a number of different regimens are approved for the treatment of metastatic breast cancer patients. However, these therapies have not changed the outcome of patients affected by this malignancy. As a consequence, the balance between chemotherapy-induced side effects and relief of cancer-related symptoms must be carefully considered in this setting. Gemcitabine is an antimetabolite that is incorporated as a triphosphate into DNA. As a single agent, it yields responses rates ranging from 14% to 37% in chemotherapy-naïve patients and from 12% to 30% in patients previously treated with anthracyclines and/or taxanes. In combination with paclitaxel, it produces a significantly higher response rate (41.4% vs. 26.2%), longer time to progression (6.1 vs. 4 months) and significantly higher overall survival (18.6 vs. 15.8 months) than paclitaxel alone. In addition, a phase III study revealed that gemcitabine plus docetaxel is as effective as capecitabine plus docetaxel, but causes significantly less non-haematologic toxicity. Lastly, in another phase III trial, progression free survival was significantly longer with the combination of gemcitabine plus vinorelbine than with vinorelbine alone (6 vs. 4 months), but without a significant difference in overall survival; the incidence of haematologic toxicity was higher in the group treated with combined therapy. Novel gemcitabine combinations are being investigated in phase II studies.

This paper deals with the aerodynamic exploration analysis of innovative unusual vehicle concepts, suitable for a manned Mars entry, aiming to support design studies of planetary entry systems. In this framework, two lifting body (LB) configurations have been analyzed so far. Several fully three-dimensional (3D) computational fluid dynamics (CFD) analyses, both for a perfect gas model and for a nonequilibrium reacting gas mixture model, have been performed. The flowfield environment past the exploration vehicle for an assigned Mars entry scenario has been addressed. To this end, a wide range of flow conditions, including different angles of attack (AoA), various Mach numbers, and Reynolds numbers, have been investigated. Results reported in the paper are useful for providing numerical data for further understanding the fluid dynamics processes, as those of high enthalpy flow and vehicle shape effects, involved in the design analysis of LB vehicles for the exploration of Mars.

Purpose: To verify the experience of the GOIM in the treatment of advanced colorectal cancer patients with the FOLFIRI combination therapy. Patients and methods: Patients entered in three consecutive trials of the GOIM (protocols no. 9706, 9901, and 2301) were reported in this analysis. A total of 287 chemotherapy-naive patients were treated with FOLFIRI regimen: Irinotecan 180mg/m 2 on day 1 with LV5FU2 regimen (LV at 100mg/m 2 administered as a 2-hour infusion before FU at 400mg/m 2 as an intravenous bolus injection, and FU at 600mg/m 2 as a 22-hour infusion immediately after 5FU bolus injection on day 1 and 2); the treatment was repeated every 2 weeks. Results: 287 patients entered in these three trials, and 264 (92%) were evaluable for response. The overall response rate was 34.5% (95% confidence interval [CI]: 29% to 40%). When only assessable patients were analyzed, overall response rate was 37% (95% CI: 31% to 43%). Median time to progression, median duration of response and survival were 7 months, 10.5 months and 14 months, respectively. All but three patients were evaluable for toxicity which was globally mild; grade 3‐4 toxicity was uncommon, and gastrointestinal disturbances were the most common. Conclusions: FOLFIRI regimen is effective and well-tolerated as first-line treatment in patients with advanced colorectal cancer. Further studies needed to evaluate the improvement in results with the addition of new drugs to this combination therapy.

Several numerical analyses have been conducted to examine the effects of some state-of-the-art chemistry models on the aerothermodynamic performances of hypervelocity blunt vehicles. At the beginning, the reentry flight scenario has been defined, and the aeroheating environment has been analyzed, for the achievement of a realistic representation of the flight trajectory for a preliminary estimation of real gas effects. After the definition of the freestream conditions in which the peak heating occurs, several set of reactions have been analyzed in numerical computations. In this way, it has been possible to carry out a dispersion analysis, due to the aerothermochemical model, of the vehicle flight scenario. In detail, it has been analyzed the influence of the technique for the aerodynamic database definition (engineering, panel, and viscous computations methods) on remarkable parameters like peak heating, thermal load, crossrange, and downrange. Then, the analysis of different kind of reactions allows to investigate the reaction mechanism and to understand the main dissociation reactions occurring in high energy flows.

Introduction: Platinum-based chemotherapy is the gold standard in advanced non-small cell lung cancer (NSCLC), although with relevant toxic effects. Both docetaxel (DCT) and gemcitabine (GEM) have shown activity as single agent in advanced NSCLC with a different toxicity profile and a lack of cross-resistance. Materials and methods: From April 2000 to May 2001, 47 consecutive patients were enrolled in a multicenter phase II trial. Main inclusion criteria included untreated patients with histologically confirmed NSCLC, age⩽70 years, stage IIIB/IV, Eastern Cooperative Oncology Group performance status (PS) 0–2, measurable disease, adequate hematologic, cardiac, hepatic and renal functions, and written informed consent. Treatment schedule consisted of DCT at the dosage of 50 mg/m 2 with conventional steroid premedication and GEM at the dosage of 2000 mg/m 2 . Both drugs were administered every 2 weeks without prophylactic use of growth factors. Results: Enrolled patients included 40 males and seven females with a median age of 65 years, and a median PS 1. There were 26 squamous carcinomas, 13 adenocarcinomas, and eight others, 13 stage IIIB and 34 stage IV. A total of 371 cycles were administered. Overall 18 partial responses were observed (38.3%); 14 patients were considered as stable disease and 13 showed progressive disease. Two treatment-not related deaths occurred before the first disease evaluation was performed. Median duration of response was 6 months (range 2–10) and median duration of survival was 10.5 months (range 1–25+). One year survival probability was 38% (95% CI 25–54%). In a statistical analysis responses were independent to histology or stage. Grade 3–4 toxicity, according NCI criteria, was mild with neutropenia in eight patients (17%), anemia in two patients (4%). Asthenia affected two patients and mucositis occurred in one patient. Conclusions: In our experience the biweekly combination of DCT and GEM is active and well tolerated and can be administered without G-CSF primary prophylaxis reducing treatment costs. It should be considered as a promising alternative to more toxic platinum-based regimens.

PURPOSE: This phase II multicenter trial was aimed at investigating the activity of epirubicin-vinorelbine combination as first-line chemotherapy in metastatic breast cancer patients. PATIENTS AND METHODS: Ninety-seven patients with metastatic breast cancer and no prior exposure to anthracyclines received the following regimen: epirubicin 100 mg/m2 by intravenous (IV) bolus infusion on day 1 plus vinorelbine 25 mg/m2 by 30-minute IV infusion on days 1 and 5, every 3 weeks for up to eight cycles. All patients also received granulocyte colony-stimulating factor (G- CSF) on days 7 to 12 of every cycle. RESULTS: Objective responses, confirmed at least 4 weeks after the first documentation, were observed in 65 out of 92 assessable patients (70.6%; 95% CI, 62% to 80%). Disease remained stable in 17 patients (18.5%). Responses were observed in all disease sites, being 94% in soft tissue, 60% in bone, and 66% in visceral disease. Median time to response, median duration of response, median time to progression, and median overall survival were 2, 9, 10, and 26 months, respectively. The dose-limiting toxicity was neutropenia, which was grade 4 in 36% of the patients, and was accompanied by fever in 26% of the cases. Grade 3 to 4 mucositis was encountered in 28% of the patients. Other toxicities were mild to moderate. No cardiotoxicity was observed. CONCLUSION: The epirubicin-vinorelbine combination with G-CSF support has been shown in this study to be highly active as first-line treatment of metastatic breast cancer patients, with significant although transient toxicity. This justifies further evaluation in the neoadjuvant setting and in early-stage breast cancer.

In the context of chronic physical illness, such as breast cancer, depression is associated with increased morbidity, longer periods of hospitalization, and greater overall disability. Prompt diagnosis and effective treatment is. therefore, essential. Several small studies have established the efficacy of tricyclic antidepressants (TCAs) in this setting, and the selective serotonin reuptake inhibitors (SSRIs) would appear to be an alternative therapeutic option because of their established efficacy and better tolerability profile. This was a multicenter. double-blind, parallel-group study in which 179 women with breast cancer were randomized to treatment with either the SSRI paroxetine (20-40 mg/day), or the TCA, amitriptyline (75-150 mg/day). After 8-weeks treatment, depressive symptomatology had improved markedly and to a similar extent in both groups on the Montgomery Asberg Depression Rating Scale. Clinical global impression (CGI) Global improvement and Patient global evaluation scales indicated that patients were minimally to much improved at study endpoint: a change from moderately/mildly ill to borderline ill on the CGI severity of Illness scale. A steady improvement in quality of life was also observed in both groups. There were no clinically significant differences between the groups. In total, 47 (53.4%) patients in the paroxetine group and 53 (59.6%) patients in the amitriptyline group had adverse experiences, the most common of which were the well-recognized side-effects of the antidepressant medications or chemotherapy. Anticholinergic effects were almost twice as frequent in the amitriptyline group (19.1%) compared with paroxetine (11.4%). This study has demonstrated that paroxetine is a suitable alternative to amitriptyline for the treatment of depression in patients with breast cancer.

Fifty-five consecutive patients with metastatic breast cancer (MBC) (n = 57) were treated with a combination of levofolinic acid (I-FA) 100 mg/m2 plus 5-fluorouracil (5-FU) 340 mg/m2 i.v. on day 1-3, cyclophosphamide (CTX) 600 mg/m2 i.v. on day 1 and mitoxantrone (DHAD) 12 mg/m2 i.v. on day 1. DHAD dose was progressively escalated by 2 mg/m2/cycle up to 18 mg/m2 in the absence of dose-limiting toxicities. Granulocyte colony stimulating factor (G-CSF) was given s.c. in order to prevent neutropenia. DHAD dosage could be increased to 18 mg/m2 in 66 out of 317 cycles of chemotherapy (21%). In most patients the dose-limiting toxicity was represented by myelosuppression. A statistically significant correlation was found between median white blood cell (WBC) or absolute neutrophil count (ANC) nadir and DHAD dose level. Moreover, a statistically significant correlation was observed between the number of chemotherapeutic cycles, nadir ANC and WBC, and the occurrence of anemia and thrombocytopenia of increasing severity. These data suggest the occurrence of progressive cumulative bone marrow toxicity. Although patients who reached different DHAD levels showed differences in mean dose intensity, such differences were not statistically significant. No correlation was found between the increase in dose intensity and type, rate or duration of objective responses. In patients with metastatic breast cancer the overall response rate was 72% (95% CL 57-84%) with a 18% complete response rate. Median duration of response was 12 and 11 months, respectively, for complete and partial responses. Projected median survival of the whole series of patients with MBC was 18 months. These data demonstrate that the combination of 5-FU with I-FA, CTX and DHAD is very active against MBC. G-CSF use allows the increase DHAD dosage up to 18 mg/m2/cycle, but its use may be linked to the occurrence of sometimes severe cumulative hematological toxicity.

SummaryA total of 101 patients with advanced colorectal cancer in two consecutive Southern Italian Oncology Groups (GOIM) studies (8501 and 8801- arm A) were treated with a sequential combination of high dose methotrexate (HDMTX) and fluorouracil (FU). Of the 92 eligible patients, 2 achieved complete response (2%) and 27 partial response (30%), with a median duration of 7 months. When classified according to the time interval between administration of the two drugs, retrospective analysis showed significant improvement (p = 0.04) in overall survival in the shorter time interval group (6 hours). The observed toxicities were generally mild and transient. Our data confirm the efficacy of the synergism between the two chemotherapeutic agents, in particular when administered with a 6-hour interval. Further studies are necessary to establish the possibility of enhancing the efficacy of sequential treatment with the modulation of FU with high-dose folinic acid.

Summary Purpose A phase III randomized trial was carried out to compare two schedules of the vinorelbine (VNR)–cisplatin (CDDP) regimen in patients with locally advanced unresectable poor prognosis stage IIIB or metastatic stage IV non-small cell lung cancer. The primary endpoints were overall survival (OS) and analysis of toxicity, while secondary endpoints included response rates, time-to-progression (TTP) and quality of life (QoL). Patients and methods Eligible patients were randomized to receive: (a) VNR 25 mg/m 2 on day 1, 8 and 15 plus CDDP 100 mg/m 2 on day 1 every 4 weeks or (b) VNR 30 mg/m 2 on day 1 and 8 plus CDDP 80 mg/m 2 on day 1 every 3 weeks. All patients were chemotherapy-naive and had an ECOG performance status (PS) of 0–1. Results Overall 278 patients were enrolled into the trial. Overall response rate was 34% (95% CL 26–42%) in the weekly VNR/CDDP arm, and 32% (95% CL 24–40%) in patients treated with day 1–8 VNR/CDDP without any statistically significant difference. Median TTP was 4.5 and 4.6 months respectively for weekly VNR/CDDP arm and the day 1–8 VNR/CDDP one. This difference was not statistically significant (log-rank test, p = 0.818). Median OS was 9.45 and 10 months respectively for weekly VNR/CDDP arm and the day 1–8 VNR/CDDP one without statistically a significant difference (log-rank test, p = 0.259). The 1- and 2-year survival rates were 31 and 36%, and 10 and 11% respectively. The incidence of severe neutropenia (34% versus 68%; p = 0.0001) and of febrile neutropenia (5% versus 12%; p = 0.026), as well as the rate of therapy omissions (10% versus 24%; p = 0.0037) were higher in the weekly VNR/CDDP arm than in the day 1–8 VNR/CDDP one. The weekly VNR/CDDP regimen was associated with a lower received dose intensity in a statistically significant fashion (9% versus 22%; p = 0.0001) and with a lower non-statistically significant quality of life score as compared to the day 1–8 VNR/CDDP schedule. Conclusions The combination of day 1–8 VNR plus CDDP every 3 weeks is less toxic and better tolerated than the regimen of weekly VNR plus CDDP every 4 weeks. The two schedules are equivalent in terms of overall response rate, median time-to-progression and overall survival. The combination of VNR on day 1–8 plus CDDP every 3 weeks may be considered as a reference regimen for the treatment of patients with advanced disease and those who deserve a postoperative therapy, and for future studies.

Summary Approximately 20–25% of patients with limited small cell lung cancer (SCLC) can be cured with an aggressive approach (chest radiation concomitant with chemotherapy) followed by prophylactic cranial irradiation (PCI) to a total dose of 30–36 Gy with 3–2 Gy per fraction, five fractions per week. Steroid prophylactic therapy with dexamethasone is usually prescribed during PCI to minimize acute radiation induced brain oedema. This approach may induce an immunosuppressive condition leading to a reactivation of an endogenous latent Herpes simplex virus and severe or fatal acute encephalitis may occur as our report will show. A 55-year-old man affected by locally advanced SCLC was referred to our institution after four cycles of chemotherapy with a good partial remission. Chest radiation started concomitantly with two cycles of chemotherapy followed by PCI 36 Gy total dose and dexamethasone 8 mg i.m. daily. Fifteen days after PCI completion the patient developed acute neurological symptoms of confusion, cognitive impairment, fever with shaking requiring severe sedation therapy. Twenty-five days later MRI T1 weighted images showed haemorrhagic streaked lines on cortical convolutions of the right cerebral hemisphere and diffuse oedema suggestive of herpetic encephalitis. The DNA consensus test on cerebrospinal fluid (CSF) was positive for Herpes simplex virus 1 infection (HSV-1). A diagnosis of herpetic encephalitis HSV-1 was made. Antiviral therapy with high doses of acyclovir was prescribed but symptoms did not ameliorate leading to a comatose state. The patient died 55 days after the end of PCI. In eligible SCLC patients, PCI is an important part of an aggressive therapeutic approach that improves overall and disease free survival decreasing the risk of relapse in the brain. A primary infection or a reactivation of an endogenous latent HSV in brain parenchyma under steroid therapy concomitant to brain irradiation may compromise these benefits.

Background The aim of the study was to verify the efficacy and safety of the addition of celecoxib to FOLFIRI combination therapy in patients affected by advanced colorectal cancer. Patients and methods Eighty-one chemotherapy-naive patients entered in this randomized phase II trial of the GOIM (protocol no. 2301). Patients were randomized to receive FOLFIRI regimen (arm A): irinotecan 180 mg/m2 on day 1 with LV5FU2 regimen (LV at 100 mg/m2 administered as a 2-h infusion before FU at 400 mg/m2 as an intravenous bolus injection, and FU at 600 mg/m2 as a 22-h infusion immediately after 5-FU bolus injection on day 1 and 2); or FOLFIRI plus celecoxib 400 mg twice daily for 14 days (arm B). Both treatments were repeated every 2 weeks. Results Seventy-seven patients (38 in arm A and 39 in arm B) were evaluable for response. The overall response rate was 41% in arm A (95% CI 27% to 57%) and 35% in arm B (95% CI 20% to 50%). When only assessable patients were analyzed, overall response rate was 45% in arm A (95% CI 29% to 61%) and 36% in arm B (95% CI 21% to 51%). Median time to progression, median duration of response and survival were, respectively, 8 months, 9 months and 16 months in arm A, and 7 months, 9 months and 19 months in arm B. All patients were evaluable for toxicity, which was globally mild in both arms; grade 3–4 toxicity was uncommon, and gastrointestinal disturbances were the most common. Conclusions FOLFIRI regimen is effective and well-tolerated as a first-line treatment in patients with advanced colorectal cancer. The addition of celecoxib to FOLFIRI regimen does not improve results.

Purpose: we carried out a phase III randomized trial to compare vinorelbine–cisplatin regimen to gemcitabine–cisplatin regimen, and to a sequential administration of gemcitabine–ifosfamide followed by vinorelbine–cisplatin or the opposite sequence of vinorelbine–cisplatin followed by ifosfamide–gemcitabine according to the ‘worst drug rule’ hypothesis in patients with locally advanced unresectable stage IIIB or metastatic stage IV non-small cell lung cancer. The primary endpoint was survival parameters, while secondary endpoints included analysis of response rates and toxicity. Patients and methods: patients were randomized to receive: (a) gemcitabine 1000 mg/m2 on days 1, 8 and 15 plus ifosfamide 1500 mg/m2 on days 8–12 with mesna uroprotection (GI regimen) followed by vinorelbine 25 mg/m2 on days 1 and 8 plus cisplatin 100 mg/m2 on day 1 (GI→VC regimen); (b) the opposite sequence (VC→GI); (c) vinorelbine plus cisplatin as above described (VC regimen); or (d) gemcitabine 1400 mg/m2 on days 1 and 8 plus cisplatin 100 mg/m2 on day 8 (GC regimen). All regimens were given every 4 weeks. All patients were chemotherapy naive and had a ECOG PS 0-2. Results: 400 patients were enrolled into the trial. Interim analysis after inclusion of 243 patients showed that ORR were 19% in the GI→VC arm, 32% in the inverse sequence arm (CV→GI), 42% in the VC arm, and 30% in the GC arm. The VC arm was statistically superior over the GI→VC arm (p=0.0074), but not over the other regimens. Median TTP was 3.1 months in the GI→VC arm versus 5.0 months in the VC→GI arm (p=0.014). For these reasons the GI→VC and VC→GI arm were closed since the ‘worst drug rule’ hypothesis was rejected. Accrual in the VC and GC arms continued up to 140 and 138 patients respectively. Final ORR were 44% for the VC regimen (4 CR), and 34% for the GC regimen (1 CR). This difference was statistically significant (p=0.032). OS was 9.0 and 8.2 months, respectively, with no statistically significant difference. The 1-year survival rate was 24 and 20%, respectively for VC and GC regimens. As expected the incidence of phlebitis was higher in the VC arm, while thrombocytopenia, flu-like syndrome and asthenia were more frequent in the GC arm. Conclusions: the results of this trial indicate that the combination of vinorelbine and cisplatin and that of gemcitabine and cisplatin are equivalent in terms of median TTP and OS, although the vinorelbine–cisplatin regimen is associated with a higher ORR. Both regimens may be considered as reference treatments for future studies. Moreover, our data reject the ‘worst drug rule’ hypothesis of sequential treatments in NSCCL at least with the combination used in this study.

Purpose: To compare a regimen of vinorelbine and cisplatin (VC) to the combination of mitomycin, vindesine, and cisplatin (MVP) in patients with stage IIIB or stage IV non-small cell lung cancer (NSCLC). The main endpoits were analysis of objective response rates, toxicity, time to progression, and overall survival. Patients and methods: 247 eligible patients were randomized to receive (a) vinorelbine 25 mg/m 2 intravenous bolus on days 1and 8 plus cisplatin 100 mg/m 2 on day 1 every 4 weeks, or (b) mitomycin c 8 mg/m 2 i.v. on day 1, vindesine 3 mg/m 2 i.v. on days 1, 8, 15 and 22, plus cisplatin 100 mg/m 2 on day 1 every 4 weeks. In subsequent cycles vindesine was given every other week. For both treatments a maximum of six cycles was planned. Patients with performance status 0–2 according to the ECOG scale were enrolled. Response and toxicity were evaluated according to the WHO criteria. Analysis of clinical efficacy was performed according to an intent-to-treat analysis. Results: No statistically significant differences in clinical efficacy were observed between the two chemotherapy regimens. The overall objective response rates were 39% (95% CL, 31–49%) in the VC arm and 42% (95% CL, 33–51%) in the MVP arm ( P =0.13). Median time to progression was 4.2 and 4.5 months for the MVP arm and the VC arm, respectively. Median overall survival was 7 months in the VC arm and 8 months in the MVP one (log–rank test, P =0.898). These differences were not statistically significant. However, leukopenia and thrombocytopenia were significantly higher in the MVP arm than in the VC ( P =0.0001; P =0.0002). Grade 3 alopecia was more frequent in the MVP arm than in the VC one ( P P =0.037). Conclusion: Data achieved in this study suggest that the vinorelbine–cisplatin doublet is similar to the three-drug MVP regimen in term of overall response rate, time to progressive disease, and overall survival. However, hematological toxicity and alopecia are more frequent and severe in the MVP regimen which therefore appears to be less tolerable than the VC regimen. The combination of vinorelbine and cisplatin may be considered as a reference treatment for future studies on the treatment of advanced NSCLC.

A total of 71 patients with advanced gastric carcinoma were randomized to receive either folinic acid + fluorouracil (arm A) or the same combination with the addition of 4-epidoxorubicin (arm B). Of the 62 evaluable patients (31 in both arms), six patients achieved a CR (10%) and 16 a PR (25.5%) with an overall response rate of 35.5% (29% in arm A and 42% in arm B; p = .28). Median duration of response was 6 and 7 months for arm A and B, respectively (p = .6). Responder patients showed a significantly better median survival duration than nonresponders (p = .01); in arm B the median survival duration was 16 months for responder patients in contrast to 7 months for nonresponders (p = .004). Toxicity was mild without significant differences between the two groups. There was one death due to hematological toxicity (arm A). The EPI-FA-FU combination appears effective and well tolerated with the additional advantage of being able to be administered in the outpatient clinic.

3559 Background: Cetuximab is an IgG monoclonal antibody targeting the EGFR showing to be effective both as single agent or in combination with Irinotecan (CPT-11) or Irinotecan/FU/FA in patients (pts) with EGFR-expressing metastatic colorectal cancer (CRC) in the first and second/subsequent-line setting. The current trial was designed to evaluate the efficacy and the safety of Cetuximab plus Folfox-4 as first -line treatment. The main objective was the percentage of confirmed objective response rate. Methods: Chemonaivepts with non-resectable metastatic CRC and expressing EGFR were treated with Cetuximab (400 mg/m2 week 1 and 250 mg/m2 weekly thereafter) plus Folfox-4 (every 2 weeks: Oxaliplatin 85 mg/m2, day 1; FA 100 mg/m2 2h, simultaneously with OH-P, and FU 400 mg/m2 iv bolus followed by 600 mg/m2 iv for 22h on days 1 and 2). The first evaluation of disease status (Recist criteria) was performed after the first 4 cycles and confirmed after one month. The treatment was continued until a maximum of 12 cycles of chemotherapy; the maintenaice with Cetuximab was permitted. Preliminary results: On the 65 screened pts, 47 (72%) had EGFR-expressing metastatic disease and were enrolled. Their main characteristics were: median Ecog PS 0; median age 66 yrs (range 43–74); main sites of disease: liver 31, lung 12, lymph-nodes 3, others 8. To date twenty-two pts are evaluable for activity and 27 for toxicity; 2 pts are not evaluable and 25 are too early. We observed 16 PR (72.7%), 5 NC (22.7%) and 1 PD (4.6%) for an ORR of 72.7% and a TGCR of 95.4%; the confirmed PR were 15 (68%). To date 2 pts undergone surgery of their metastases both for lung. The main adverse events grade 3/4 (NCI criteria) were: acne-like rush 18.5%, diarrea 7%, nausea/vomiting 4% and anemia 4%. Conclusions: Our preliminary results confirm that the combination of Cetuximab plus Folfox-4 has an high activity and a good safety profile in advanced CRC pts. The study is ongoing. No significant financial relationships to disclose.

Hormonal therapy is the preferred systemic treatment for recurrent or metastatic, post-menopausal hormone-receptor-positive breast cancer. Previous studies have shown that there is no cross-resistance between exemestane and reversible aromatase inhibitors. Exposure to hormonal therapy does not hamper later response to chemotherapy. Patients with locally advanced or metastatic, hormonal receptor positive or unknown, breast cancer were treated with oral anastrozole, until disease progression, followed by oral exemestane until new evidence of disease progression. The primary end point of the study was clinical benefit, defined as the sum of complete responses (CR), partial responses (PR) and > 24 weeks stable disease (SD). In all, 100 patients were enrolled in the study. Anastrozole produced eight CR and 19 PR for an overall response rate of 27% (95% CI: 18.6-36.8%). An additional 46 patients had long-term (> 24 weeks) SD for an overall clinical benefit of 73% (95% CI: 63.2-81.4). Median time to progression (TTP) was 11 months (95% CI: 10-12). A total of 50 patients were evaluated for the second-line treatment: exemestane produced one CR and three PR; 25 patients had SD which lasted ≥ 6 months in 18 patients. Median TTP was 5 months. Toxicity of treatment was low. Our study confirms that treatment with sequential hormonal agents can extend the period of time during which endocrine therapy can be used, thereby deferring the decision to use chemotherapy. © 2005 Cancer Research UK.

3656 Background: The combination of Irinotecan (CPT-11) at 180 mg/mq combined with LV5FU2 (FOLFIRI - Douillard regimen), represents a standard first-line therapy for ACRC pts. Celecoxib is a selective anti-Cox2 compound with antineoplastic properties such as angiogenic inhibition and apoptosis induction. Experimental data demonstrated the synegistic interaction of Celecoxib with CPT-11 and Fluorouracil (FU). Taking into account these data the Gruppo Oncologico dell’Italia Meridionale (GOIM), started a phase II randomized study to compare the activity and toxicity of FOLFIRI regimen alone (arm A) or with the addition of Celecoxib (arm B) in ACRC pts. Methods: Pts with hystological/cytological diagnosis of colorectal cancer, measurable disease, ECOG PS ≤ 2, age ≥ 18 and ≤ 75 years, entered into this trial. Pts were randomized to receive: Arm A: CPT-11 180 mg/mq on day 1 and LV5FU2 regimen (Folinic acid 100 mg/mq in 2-hr iv infusion, FU 400 mg/mq iv bolus, and FU 600 mg/mq in 22-hr iv infusion on day 1 and 2...

To evaluate the possibility that a low modulating dose of IFN can enhance the anti-tumor effect of FA-FU combination therapy, patients (pts) with ACC were randomized to receive either FA (I-isomer form) 100 mg/m 2 iv just before FU 375 mg/m 2 iv for five consecutive days alone (A), or with IFN-alpha2b 3 MU for seven consecutive days, starting two days before FA-FU administration (B). Both regimens were repeated every three weeks. Two hundred-three pts were entered in the study. Actually, 156 (79 arm A, and 77 arm B) are evaluable for response, and 23 are early to evaluate. The main characteristics of the evaluable pts were: sex (M/F): A:48/31. B:46/31; median age (A/B): 64/62 yrs; primary tumor site (colon/rectum): A:43/36, B:51/26; metastatic sites (A/B): liver 61/62, lung 13/16, lymph node 15/14, multiple sites 39/35. Tumor response rates (CR + PR) were 23% in the FA-FU group (1 CR, 17 PR; 95% Cl: 17%–32%), and 30% in the FA-FU + IFN group (5 CR, 18 PR; 95% Cl: 20%–40%). No significant difference was found in overall response rate between the two arms. A total of 180 pts (A:88; B:92) are evaluable for toxicity; grade 3–4 toxicity (WHO criteria) were (A/B): leukopenia 2%/l%, diarrhea 8%/22%, mucositis 5%/12%, nausea and vomiting 2%/7%. Our preliminary results shown better response rate in FA-FU + IFN arm, but a more severe (grade 3–4) gastrointestinal toxicity.

In order to verify if an increased dose intensity is associated with higher response rate and improved survival, starting from September 1993 untreated patients (pts) with ABC were enrolled in a multicentric study of GOIM (prot. n 9304). Chemotherapy consisted (mg/mq) of L-FA 100 iv d 1–3, F 340 iv d 1–3, N 12 iv d 1 and C 600 iv d 1. G-CSF was admin-istered se at 0.5 μgr/kg from day 5 to 14. Mitoxantrone was escalated by one dose level (2 mg/mg) up to a maximum of 18 mg/mq according to nadir toxicities. Treatment was repeated every 3 weeks or was moved up in the presence of good hemometry values. To date fifty-three pts entered into the study and 32 are evaluable for response and toxicity. The main characteristics of the evaluable pts were: median age 50 yrs; median Karnofsky PS 90; dominant site of disease: viscera 21 (62%), bone 4 (12%), soft tissue 9 (26%) of which 2 pts with locally advanced breast cancer (LABC), multiple site of disease 22 (65%). Globally 4 CR and 19 PR were observed for an ORR of 68%; there were 8 SD and 3 PD. Both the LABC pts achieved a PR and underwent to the surgery. Median duration of response was 9 months (range 4+–17+). A total of 188 cycles were administered: in 107 cycles (57%) it was possible to increase the mitoxantrone dosage and in 28 cycles (15%) the maximal dosage of 18 mg/mq was reached. In 43 cycles (23%) the internal among cycles was reduced. Toxicity was mild and gastrointestinal and hematological toxicity of grade (G) 3–4 was not observed. At nadir the most important hematological toxicity was leucopenia (85%), followed by anemia (76%) and thrombocytopenia (53%). Alopecia of grade G3 was seen in only 3 cases. The study is ongoing, but preliminary data show the F-FNC combination as a well tolerated and effective form of palliative treatment in ABC.

Sixty-four consecutive patients with locally advanced (n = 7) or metastatic breast cancer (n = 57), were treated with a combination of laevofolinic acid 100 mg m-2 plus 5-fluorouracil 340 mg m-2 i.v. on days 1-3, cyclophosphamide 600 mg m-2 i.v. on day 1 and epirubicin 90 mg m-2 i.v. on day 1. Epirubicin dose was progressively escalated by 10 mg m-2 per cycle up to 120 mg m-2 in the absence of dose-limiting toxicities. Granulocyte colony-stimulating factor (G-CSF) was given subcutaneously in order to prevent neutropenia. Epirubicin dosage could be increased to 100 mg m-2 in 53 patients (87%), to 110 mg m-2 in 31 patients (51%) and to 120 mg m-2 in 18 cases (30%). In most patients the dose-limiting toxicity was represented by myelosuppression. A statistically significant correlation was found between median white blood count (WBC) or absolute neutrophil count (ANC) nadir and epirubicin dose level (P = 0.009; P = 0.008). Moreover, a statistically significant correlation was observed between the number of chemotherapeutic cycles, nadir ANC and WBC and the occurrence of anaemia and thrombocytopenia of increasing severity. These data suggest the occurrence of progressive cumulative bone marrow toxicity. Although patients who reached different epirubicin levels showed differences in mean dose intensity, such differences were not statistically significant. No correlation was found between the increase in dose intensity and type, rate or duration of objective responses. In patients with metastatic breast cancer the overall response rate was 72% (95% CL 66-78%) with a 25% complete response rate. Median duration of response was 10 and 13 months respectively for complete and partial responses. All patients with locally advanced breast cancer had an objective response and underwent radical mastectomy. Projected median survival of the whole series of patients with metastatic breast cancer was 20 + months. These data demonstrate that the combination of 5-fluorouracil with laevofolinic acid, cyclophosphamide and epirubicin is very active against metastatic breast cancer. Use of G-CSF allows epirubicin dosage to be increased up to 120 mg m-2 cycle-1, but its use may be linked to the occurrence of sometimes severe cumulative haematological toxicity.

© 2017, American Institute of Aeronautics and Astronautics Inc, AIAA. All rights reserved. As a fundamental step towards the development of a civil high-speed transport concept, the European Community (EC) co-funded HEXAFLY-INT international project (with partners from Europe, Russian Federation, Brazil and Australia), has the aim to design, manufacture and test in flight an innovative gliding hypersonic vehicle, based on the configuration developed in previous EC co-funded projects LAPCAT I, II and HEXAFLY. The flight experiment is focused on a self-controlled glider configuration characterized by high aerodynamic efficiency and equipped with several breakthrough technologies on-board, in order to provide valuable aerodynamic and aero-structural flight data to validate methods and technologies used to design the hypersonic vehicle. In this framework, this paper provides a detailed overview on research efforts carried out in assessing the aerodynamic performance of the expendable Experimental Flight Test Vehicle under development in the programme. Aerodynamic results are obtained by means of a massive number of CFD simulations of increasing level of accuracy and through an experimental test campaign carried out at TsAGI in their T-116 wind tunnel facility. ispartof: Proceedings of AIAA 2017 ispartof: 21st AIAA International Space Planes and Hypersonics Technologies Conference location:Xiamen, China date:6 Mar - 9 Mar 2017 status: published

Copyright © 2017 ASME. Over the last years, innovative concepts of civil high-speed transportation vehicles were proposed. In this framework, the Hexafly-INT project intends to test in free-flight conditions an innovative gliding vehicle with several breakthrough technologies on-board. This approach will help to gradually increase the readiness level of a consistent number of technologies suitable for hypervelocity flying systems. The vehicle design, manufacturing, assembly and verification is the main driver and challenge in this project. The prime objectives of this free-flying high-speed cruise vehicle shall aim at a conceptual design demonstrating a high aerodynamic efficiency in combination with high internal volume; controlled level flight at a cruise Mach number of 7 to 8;an optimal use of advanced high-temperature materials and structures. Present research describes the aero-thermal design process of the Experimental Flight Test Vehicle, namely EFTV. The glider aeroshape design makes maximum use of databases, expertise, technologies and materials elaborated in previously European community co-funded projects LAPCAT I & II [1][2], ATLLAS I & II [3][4] and HEXAFLY [5]. The paper presents results for both CFD and Finite Element aero-thermal analysis, performed in the most critical phase of the experimental flight leading to the selection of materials for the different components and to a suitable Thermal Protection System. ispartof: PROCEEDINGS OF THE ASME INTERNATIONAL MECHANICAL ENGINEERING CONGRESS AND EXPOSITION, 2017, VOL 1 vol:1 ispartof: ASME International Mechanical Engineering Congress and Exposition location:Tampa, FL date:3 Nov - 9 Nov 2017 status: published

The current perspectives in the aerospace sector require a particular attention for the analysis of several phenomena involving the coupling between the mechanical behaviour and the other physics fields such as the fluid-structure interaction problem. This issue is particularly felt in the design of Reusable Launch Vehicle (RLV) since, during reentry, such kind of vehicles carries large quantities of Main Engine Cut Off (MECO) residual propellants. The management of the residual propellant remaining in the reusable stage after MECO during a nominal mission is a crucial point for the design with respect to: dimensioning and weight, landing safety issues, and post-landing procedures. Generally speaking, the motion of a fluid inside the RLVs’ tank (e.g. propellant sloshing) can affect the stability of the spacecraft and, when it is too much violent, could damage the structure, generating the vehicle failure. As a consequence, the structural design of propellant tanks should take adequately into account for the propellant slosh load in combination with all other loads and inputs. Therefore, there is a need for explaining what happens with a fluid subjected to loading environment of a typical RLV reentry trajectory (Bucchignani et al. 2008). Sloshing of propellants describes the free-surface oscillations of a fluid in a partially filled tank. These oscillations are due to lateral and longitudinal or angular motions of the spacecraft, as well as, when there are no tank disturbances, to the interchange of kinetic energy and the potential energies due to gravitational and surface tension forces (NASA, 1968). In particular, these free oscillations may persist since the damping provided by the wiping of the fluid against the tank’s wall is negligible. Therefore, forced oscillations result in large free-surface waves. The magnitude of propellant sloshing depends upon the following parameters: acceleration field, propellant properties, tank geometry, effective dumping, height of propellant in the tank, and perturbing motion of the tank (NASA, 1968). In recent times, the phenomenon of sloshing in partially filled tanks has been widely investigated by means of analytical methods or experimental techniques. The problem of small horizontal oscillations has been extensively investigated in the past, using analytical and experimental methods (Faltinsen et al., 2000) (Faltinsen et al., 2001). It has been shown that the response is the same as that of the undamped Duffing equation and changes from soft-spring (decreasing amplitude with increasing frequency) to hard-spring (increasing

This paper deals with the aerodynamic performance analysis of the expendable Experimental Flight Test Vehicle under development in the seventh framework programme, namely HEXAFLY-INT. A mission scenario, the different flight segments and events to which the payload is exposed to are described and justified. This allowed the definition of the aerothermo-mechanical loads required to conceptually design all elements on board of the vehicle. This flying test bed is a self-controlled glider configuration that shall face a hypersonic flight starting at about Mach 8, just after the separation from the experimental support module at about 50 km altitude, up to vehicle loss. During this flight, several experiments shall be carried out. The appraisal of the vehicle aerodynamic performance is needed for Flight Mechanics and Guidance, Navigation and Control analysis. In particular, hinge line moments for the EFTV’s aileron are also addressed to design the actuation line and to select the actuator device itself. The vehicle made maximum use of databases, expertise, technologies and materials elaborated in previously European community co-funded projects ATLLAS I & II, LAPCAT I & II, and HEXAFLY.

This paper deals with the design trade-off activities undertaken to provide a trim-able, a statically and dynamically stable vehicle configuration able to perform a nominal experimental scramjet-propelled flight. The flight control activities and their impacts on vehicle layout and global aerodynamic performance are also addressed. In particular, different competing aeroshapes have been investigated to assess the best one camplyant with project requirements. In this framework, trade-off results in terms of: setup and/or analysis of aero-propulsive databases; design loops for the aileron (shape, span, length); design loops for the vertical tail (shape, size, toe-angle); analysis of aerodynamic performances; analysis of longitudinal trimming conditions; sensitivity to centre of gravity position of static longitudinal stability and trimming conditions; static stability analysis (for longitudinal and lateral-directional flight) in clean and flapped configuration, static margins (pitch, roll, yaw); dynamic stability analysis with a focus on roll-yaw coupling (linearized model analysis and Dutch-Roll period evaluation); characterization of hinge-moments; and preliminary selection of flight control equipment are provided and described in detail in the paper.

Some conceptual aeroshapes, designed to fit the constraints of VEGA launcher fairing and with the capability of a conventional landing, were studied by means of numerical tools from hypersonic to subsonic speed conditions. Aerodynamic coefficients were also compared to flight proven or preliminary designed vehicles with similar requirements on re-entry flight. Aerodynamic performances were evaluated with engineering tools and CFD code in order to drive the choice of a more suitable aeroshape for a whole re-entry system development.

This paper deals with the computational fluid dynamics analysis of a capsule entering the Earth atmosphere, at the end of a sample return mission. Several two-dimensional axissymmetric simulations have been performed to assess the flowfield environment past a sphere-cone capsule, by using non-equilibrium reacting gas approximations. Heat shield ablation and effects of flow plasma radiation on capsule aeroheating are also accounted for, also if in a non-coupled approach with the flowfield analysis. the issue of aerodynamic and aerothermodynamic performance of the entry spacecraft in the framework of a superorbital re-entry scenario is addressed.

The European Space Agency project Intermediate Experimental Vehicle, leaded by Thales Alenia Space as prime contractor, is currently facing the development phase. In this framework the European Space Agency is coordinating a series of technical assistance activities aimed at verifying and supporting the vehicle design and development process. As for all the ESA project this technical support is provided both by ESA TEC directorates and by National Organizations, with the supervision and coordination of the ESA IXV project. Namely, for IXV the Italian Space Agency (ASI) is operating this assistance activity by means of the technical support of the Italian Aerospace Research Center (CIRA). Among the topics object of the technical assistance activities carried out by CIRA, this paper deals with the development of an Aerodynamic Database, independent from the one developed by the industrial team, to be used by ESA for cross checking and verification purposes.

The paper deals with the aerodynamic, aeroheating, and flight mechanics analysis of a reusable flying laboratory designed to perform a return from low Earth orbit at high aerodynamic efficiency with the aim to provide experimental data in the framework of reentry technologies. The flying test bed is a wing body with rather sharp leading edges and slender aerodynamic configuration. Several design approaches, ranging from engineeringbased to computational fluid dynamics analyses, have been addressed to assess the vehicle aero-thermal performance. To this end, aerodynamic results for a wide range of freestream flow conditions including reacting and non-reacting flow and different angles of attack have been provided and compared. Moreover, rarefaction effects on both vehicle aerodynamics and re-entry trajectory are also highlighted. Computational fluid dynamics results show that real gas effects seems to be negligible on the assessment of the concept aerodynamics; whereas flight mechanics analysis highlight that rarefaction effects, even though it has been shown that they strongly influence vehicle aerodynamics, do not significantly affect the concept return down to Earth.

Several numeric al analyses have been conducted to examine the effects of some state -of the -art chemistry models on the aerothermodynamic performances of hypervelocity blunt vehicle s. The effects of finite rate chemistry are highlighted by comparing vehicle aerodynamic pe rformance s and some flow features for the perfect gas and the reacting gas mixture results obtained with both engineering -based and well -tested high reliable Computational Fluid Dynamic and Direct Simulation Monte Carlo techniques. Aerodynamic performance s refer to coefficients of lift , drag and pitching moment , being these parameters of primary relevance for the design of trajectory and thermal protection system . In this regard, a possible Earth -entry scenario for a proposed reentry vehicle is reported and analyzed, by accounting for r eal gas effects , experienced along the atmospheric descent. Euler and Navier -Stokes computation s have been performed, in a trajectory -based design approach , by considering a capsule -type reentry vehicle, with both perfect gas and non equilibrium reacting gas models for the air ; the effect of chemical non -equilibrium on the vehicle thermal loading is pointed out .

In the frame of the Future Launchers Preparatory Program, carried out by the European Space Agency, several Reusable Launch Vehicle concepts are under investigation. In this paper the current design activities at Phase-A level, carried out by Centro Italiano Ricerche Aerospaziali, are described concerning, in particular, the two concepts RFS and LFBB (LOx/CH4). The goal has been to define the preliminary aerodynamic and aerothermodynamic data-base of each vehicle for concepts competition. To this scope, different design approaches have been addressed as engineering-based methods and Computational Fluid Dynamics. Results provided in the paper show that, for both the concepts, the aerodynamic and aerothermodynamic analyses performed through a threedimensional panel methods code, based on local surface inclination methods typical of hypersonics, are reliable for vehicles’ preliminary design scopes. Indeed, several Computational Fluid Dynamics simulations, performed at different flight conditions along the descent trajectory, show that a proper margin of about 10 % for aerodynamics and 30 % for aerothermodynamics characterize the engineering-based and CFD result comparisons.

In the frame of the Future Launchers Preparatory Program (FLPP), carried out by the European Space Agency (ESA), the VTO Hopper - Reusable Launch Vehicle (RLV) concept is investigated. The VTO Hopper is a winged Sub Orbital Single Stage (SOSS) vehicle designed for vertical take-off. It carries an expendable upper stage, able to deliver a payload up to 8 Mg in geostationary transfer orbit (GTO). After the staging at suborbital altitude (greater than 130 km), the reusable booster will follow a ballistic arc trajectory, re-enter the Earth’s atmosphere, and then perform a downrange landing. In this paper the current aerodynamic and aero-thermodynamic activities related to the launcher design are described. The goal has been to define the preliminary aerodynamic and aerothermodynamic data-bases of the vehicle. Therefore, the aero-thermal environment that the VTO Hopper will encounter along its lifting reentry flight has been analyzed, in order to provide the necessary inputs for the Thermal Protection System (TPS) design. Different design approaches have been addressed. In fact, aerodynamic and aerothermodynamic analyses have been performed starting from engineering based methods, in order to rapidly accomplish the preliminary aerothermodynamic databases thus generating a number of possible re-entry trajectories, able to fulfill the program requirements. To perform these analyses, a 3D panel methods code, based on local inclination methods typical of hypersonics, has been employed; the heat flux distributions have been, instead, evaluated by means of improved boundary layer methods. Increasing the order of complexity, a numbers of detailed 3-D Euler CFD analyses have been performed for different flight conditions along the descent trajectory.

This paper deals with the aerodynamic and aerothermodynamic analysis of a conceptual aeroshape, designed to fit the constraints of VEGA launcher fairing and with the capability to perform an end-to-end mission from launch, orbit keeping, re-entry and landing on conventional runway. Aerodynamic and aerothermodynamic performances of the aeroshape under investigation were evaluated for the whole flight scenario by means of several numerical simulations with in-house developed and commercial codes. Compilation of the numerical Data-Base, consisting of about 170 runs, and vehicle’s aerodynamics performances are shown from low subsonic to hypersonic regime. Analysis and discussion of the results with comparisons between different numerical tools and CFD codes are given.