Search

Purpose Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS). Methods The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes. Results Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival. Conclusions Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

e22161Background: There was an increasing attention to the humanization of oncological cares that focused on patients’ needs – which have a strong impact on quality of life. Cancer-related needs se...

European Community agricultural and environmental policies clearly aims at a rational use of natural resources, particularly water, and a reduction to zero in nitrogen pollution. These goals are impossible to reach without a day-by-day evaluation of the availability of water and nitrogen in the root zone. Therefore, a precise evaluation of root zone volume is essential to optimise crop water and nutrient management. A good estimation of the root zone volume requires an evaluation of the root elongation rate on three axes: depth, between rows and within rows. Horizontal root growth (between and within rows) may be assumed to be uniform and thus an uniform 3D root distribution can be calculated without taking into account differences in root density inside the root zone. Root elongation can be assessed on the basis of depth and width only. Tomato root growth rate was analysed using the data collected during the EU QUALITOM project. The project database is derived from observations made over three years in ten experimental stations located throughout the Mediterranean area and representing most of the tomato growing soil and climate conditions. Observed root growth was analysed and correlated with different soil characteristics, available water content, thermal day units accumulation, accumulated radiation and photosynthetic active radiation (PAR) in order to define some useful algorithms for modelling the soil volume occupied by roots.

Background: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. Patients and methods: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m 2 day 1, LV 100 mg/m 2 as 2 h infusion and 5-FU 400 mg/m 2 as bolus, days 1 and 2 followed by 600 mg/m 2 /day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m 2 day 1, cisplatin 75 mg/m 2 day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). Results: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85–1.17; P= 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82–1.18; P= 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. Conclusions: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. Clinical trial registration: ClinicalTrials.gov Identifier: NCT01640782.

OBJECTIVE Metastatic renal cell cancer (RCC) portends a bad prognosis, but survival is quite different among different patients. The objective of this study was to determine prognostic factors for survival with the aim to offer patients proper therapeutic options. METHODS A consecutive series of 109 metastatic RCC patients admitted to our department since 1988 was reviewed, and survival from the time of diagnosis with metastases recognition was considered. The role of age, sex, disease-free interval (DFI), ECOG performance status (PS), stage at diagnosis, grading, number and type of metastatic sites, nephrectomy, blood levels of hemoglobin, creatinine, albumin, calcium, lactate dehydrogenase (LDH), ferritin, alkaline phosphatase, triglycerides was assessed in univariate and multivariate analysis. RESULTS In our study, the following variables were found to be statistically significant at the univariate analysis (p < 0.01): DFI, ECOG PS, stage at diagnosis, grading, nephrectomy, sites of metastases, blood hemoglobin, serum albumin, calcium, LDH, alkaline phosphatase. Indeed, only an ECOG PS of 2-3 (relative risk 1.82; p = 0.003) and blood hemoglobin levels < or = 10 g/100 ml (relative risk 1.20; p = 0.017) retained their value as independent risk factors for poor survival at multivariate analysis. According to the number of independent risk factors, three groups of patients were identified, with significantly different median survival (21.7 vs. 8.6 vs. 3.5 months; log-rank test: p = 0.00004, p = 0.04126 and p = 0.00047, respectively). CONCLUSIONS Poor performance status and anemia at diagnosis of metastatic RCC predict the worst outcome in our series. These factors could be taken into account to stratify patients in clinical trails and to select the proper treatment option in oncological practice.

Interleukin-2 (IL-2) is a cytokine with proven activity against metastatic renal cell carcinoma (RCC) and malignant melanoma (MM). The intravenous administration of high-dose IL-2 is limited by important cardiovascular side effects such as hypotension, fluid retention, arrhythmias, and myocardial ischemia, which often cause dose reduction and/or treatment withdrawal. The occurrence of these toxic events is not predicted by routine pretreatment examinations. The aim of the present study was to test the reliability of serial echocardiography in predicting subsequent cardiac adverse effects in patients undergoing IL-2 administration. In 19 patients (15 men, 4 women; median age: 51 years, range 27-71 years; 10 affected by metastatic RCC and 9 affected by MM) we performed two-dimensional and Doppler echocardiography before and immediately after 28 continuous intravenous infusions (CIVI) of IL-2 at the dose of 18 MIU/m2/day for 4 days. Left ventricular systolic function and the diastolic transmitral flow pattern were assessed before and after IL-2 administration. Significant changes of two indexes of left ventricular filling were noted: a decrease of the ratio of maximal flow velocity in early diastole to that in late diastole (E/A) (basal: 1.12 +/- 0.46, mean +/- SD; posttreatment: 0.83 +/- 0.27; p < 0.01) and an increase of the percentage of the atrial contribution to left ventricular filling (basal: 37.75 +/- 11.58%; posttreatment: 49.43 +/- 16.48%; p < 0.01). Eight major cardiovascular events causing IL-2 infusion withdrawal were observed (two ischemic electrocardiographic modifications, three grade III-IV hypotension, one atrial fibrillation, one pericardial effusion, one acute heart failure). These major cardiovascular events were observed more often when an abnormal basal E/A ratio < 1.0 (p < 0.05) was found. We conclude that Doppler transmitral flow pattern analysis before and subsequent to IL-2 infusion is a useful and easily available procedure for the monitoring of cardiac modifications during CIVI IL-2 administration. It might also predict a major cardiovascular event during IL-2 administration. Patients with basal E/A ratio < 1.0 should be more carefully monitored during treatment and/or should be treated with lower IL-2 doses to avoid cardiovascular toxicity.

A randomised multi-centre phase II trial explored the role of MS in pts with MPA without progressive disease (PD) after induction chemotherapy (CT), using an observation only group (O) as calibration arm [Reni et al. Proc ASCO 2012]. The aim of this present study was to identify genetic polymorphisms related to pharmacokinetics and pharmacodynamics of sunitinib that are associated with outcome. Adult pts with pathologic diagnosis of MPA, performance status (PS) >50%, no PD after 6 months of CT were randomized to O (arm A) or MS at 37.5 mg daily until PD or a maximum of 6 months (arm B). Functional polymorphisms of 6 genes involved in sunitinib activity, metabolism and transport (VEGFA, VEGFR-2, CYP3A5, CYP1A1, ABCB1, ABCG2) were studied in genomic DNA from baseline blood samples, using PCR Taqman®-probes-based assays. Associations of genotypes with overall survival (OS) and progression-free survival (PFS) were evaluated by Log-rank test. Genotyping was successfully performed in all the DNA samples of 43 consenting pts of 55 enrolled in the trial (78%; arm A/B: 83%/73%; p = 0.39). Significantly longer OS was observed in 7 pts harbouring the ABCB1 3435TT genotype (group-1; median OS 20 months) as compared to 36 pts with 3435CC/CT genotype (group-2; median OS 7 months; p = 0.027). Median OS was 26 months in 4 group-1 arm B pts, 7 months in 15 group-2 arm B pts (p = 0.12); 16 months in 3 group-1 arm A pts and 9 months in 21 group-2 arm A pts (p = 0.67). No OS difference was observed in 28 pts harbouring the VEGFA -634GC-CC genotype (group-3; median OS 10 months) as compared to 15 pts with -634GG genotype (group-4; median OS 8 months; p = 0.15). However, median OS was 13 months in 13 group-3 arm B pts, 6 months in 6 group-4 arm B pts (p = 0.016); 9 months in 15 group 3 arm A pts and 11 months in 9 group 4 arm A pts (p = 0.67). These results suggest that polymorphisms of genes involved in expression of the main ligand for VEGFR2 (VEGFA 634G > C) and of efflux transporters (ABCB1 3435C > T) are promising candidates as predictive marker for selecting pts with MPA who may benefit of MS. Given the small sample size of these analyses, a larger confirmatory trial is necessary and appears worthwhile. Disclosure All authors have declared no conflicts of interest.

Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC. Materials and methods An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G + T arm. The primary efficacy endpoint was a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Summary PFS outcome has previously been reported; more detailed PFS as well as the initial overall survival (OS) data are presented. Results 214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer prognostic factors (older age, poorer performance status, reduced albumin) were associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G + T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G + T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340. A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G + T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G + T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G + T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240 and 59% G + T340. Conclusions The combination of G plus TH-302 improved the efficacy of G. A TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. Disclosure All authors have declared no conflicts of interest.

Systemic chemotherapy is the treatment of choice for patients with small cell lung cancer (sclc), Myelosuppression is the limiting toxicity related to most comnbination regimens in sclc, inducing substantial morbidity, frequent dose reductions, and delay in administrating subsequent cycles. Vp-16, Ifosfamide and Carboplatin are all highly active as single agents against sclc, with a ramge of objective response between 60 % and 75 %, A combination of these 3 drugs (with concurrent chest radiotherapy) showed impressive activity) > 90 % objective response rate) in a previous report by another group (Smith, 1990), at the cost of a 100 % incidence of grade III-IV neutropenia, with 7 % therapyrelated deaths and dose reductions required for 72 % of patients. The association of recombinant human granolocyte-macrophage colony stimulating factor (r-hu-gm-csf) to a chemotherapy regimen consisting of Carboplatin and Vp-16 could allow higher doses of cytotoxic drugs to be given, possibly resulting in much higher complete response rates, even in extended disease (Morstyn, 1989). Basing on these data, we designed a pilot study on the association of r-hu-gm-csf to intensive chemotherapy.

Starting from in vitro studies suggesting synergistic antitumour activity against renal cell ceancer (RCC) of recombinant interleukin-2 (rIL-2) and α-interferon (IFN), a phase II trial was initiated to test the clinical activity of this combination. The two cytokines were administered sequentially, with the aim of reducing the risk of additive toxicity and enhancing the immunological reaction against the tumour. The original treatment schedule consisted of rIL-2 18 × 10 6 U/m 2 /day by continuous intravenous infusion for 120 h days 1–5, and α-IFN 2b, at a flat dose of 9 sx 10 6 U by subcutaneous or intramuscular injection thrice in a week, from day 8 to 28. Treatment was planned to be continued for six or more 28-day cycles, depending on clinical response. 12 patients were treated according to this schedule; as some cardiovascular toxicity was experienced in this set of patients, 11 further patients were treated with half-dose rIL-2 (i.e. 9 × 10 6 U/m 2 /day). 17 out of 23 enrolled patients completed at least one cycle of treatment and were evaluated for response. We observed six major responses [one complete response (CR) + five partial responses (PR)] for an objective response rate of 35% [95% confidence interval (CI) 17–59%]. 5 additional patients achieved stabilisation of disease; one of them reached CR after surgical extirpation of a lung mass. Sites of response included lung, nodes and bone. Duration of response is 12+ months for CR; 17, 16, 12+, 9 and 9 months for PRs. Median survival is 16 months. Response was not significantly different between full-dose and half-dose rIL-2. Considering stable disease (SD) as responses, there seemed to be a higher chance of response for patients with smaller tumour burden ( P = 0.032). The toxicity of rIL-2 treatment, mainly cardiovascular, was substantial; 9 patients experienced severe cardiotoxicity, consisting of major arrhythmias, myocardial ischaemia, reduction of ejection fraction measured with heart radionuclide scan, and were excluded from continuing treatment. Other rIL-2-related toxicities forcing exclusion from the study were severe thrombocytopenia (1 case), and generalised exfoliative dermatitis requiring steroids (1 case). Otherwise, treatment was well tolerated; rIL-2-related toxicities promptly recovered after rIL-2 discontinuation in the majority of cases, and no treatment-related deaths were reported. The half-dose rIL-2 regimen was significantly less toxic in terms of hypotension ( P = 0.014), fever ( P = 0.014), oliguria ( P = 0.042), serum creatinine elevation ( P = 0.009) and prothrombin time elongation ( P = 0.038). α-IFN was not related to major toxicities. We conclude that the sequential administration of rIL-2 by continuous intravenous infusion and α-IFN by intramuscular or subcutaneous injection following our treatment schedule is feasible and active in RCC. Recombinant IL-2 9 × 10 6 U/m 2 /day seems to be equally effective and less toxic than 18 × 10 6 U/m 2 /day. However, cardiovascular toxicity remains a major problem; particularly, arrhythmias and ischaemic events are poorly predictable and preventable.

A 63-year-old woman receiving recombinant interleukin-2 (rlL-2) + lymphokine activated killer cells for metastatic renal cell carcinoma developed autoimmune thyroiditis with clinical hypothyroidism and high titer anti-thyroglobulin and anti-microsomal antibodies. The onset of thyroid dysfunction was associated with tumor regression and resulted in complete response at the end of the treatment. Cytologic and cytofluorimetric studies on thyroid tissue showed two distinct populations, mainly consisting of small lymphocytes and large thyrocytes, and the latter expressed MHC class II antigens. After completion of rlL-2 treatment, hypothyroidism gradually decreased until resolution; complete tumor remission lasted 18 months. Mechanisms underlying the association between autoimmune thyroiditis and cancer regression are discussed.

Cardiovascular toxicity related to i. v. administration of Interleukin2 (IL-2) is the main cause of treatment withdrawal and it is unpredictable on the base of standard pre-treatment evaluations including history, physical examination and EKG. We performed this study to investigate the value of Cardiac Ultra Sono Scan (CUSS) in the detection and prediction of such toxicity. The study included 19 patients (15 males, 4 females, median age: 51, tumor type: 10 advanced renal cell cancer, 9 malignant melanoma) scheduled to receive multiple cycles of IL-2 by continuous i. v. infusion at the dose of 18 MIU/m 2 /day for 96 hours. Data were recorded from 31 IL-2 infusions: a marked impairment of diastolic function was observed in all cases, but in a subset of cycles (12/31) this function was already impaired at the pre-treatment determination, and this was significantly correlated with the onset of major cardiovascular side-effects conditioning treatment discontinuation ( P P

The computerized system RTO (Registro Tumori Ospedaliero), which has been created in the National Institute for Cancer Research and Treatment of Naples (3.5OO in-patients, 6.000 hospital admission per year), is aimed at a Hospital Cancer Registry. It is implemented on SPERRY-1100/60, EXEC-8 O.S., in COBOL language, using the DPS/1100 package (Display Processing system designed for the management of display-oriented transactions in an online environment).