2080 Background: There are no phase III trials supporting the role of some treatment for relapsed glioblastomas (GBMs). GBMs are very vascularized neoplasms thus antiangiogenic therapies might obtain some antitumoral effects. Recently, an antiangiogenic such as bevacizumab has given prior encouraging results in phase II studies and is under phase III investigation. From phase II studies also low dose protracted temozolomide (LDPT) seems to have some activity at relapse. Basing on these evidences we planned a phase II trial evaluating the activity of a full oral regimen with sorafenib (S), a tyrosine kinase inhibitor with antiangiogenic activity, associated to LDPT in patients (PTS) with relapsed GBMs. METHODS Recruit able PTS (not previously treated with antiangiogenics) were enrolled in the study and received S 400mg bid plus temozolomide (T) 40mg/m2 a day continuously till unmanageable toxicity or disease progression. Disease evaluation were performed every 2 months with gadolinium enhanced MRI using RECIST criteria. RESULTS From July 2008 to October 2010, 36 patients were enrolled, 18 male, median age was 59.4 (range =36.5-75.6), ECOG PS was 0 in 2 PTS, 1 in 20 PTS and 2 in 14 PTS. All PTS had histological proven GBMs relapsed after surgery, radiotherapy and temozolomide for at least six months. Five PTS had a prior second line chemotherapy and 5 two prior lines of therapy. No PTS received prior antiangiogenic treatment. Toxicity was manageable; grade 1-2 was (Type/PTS): Hand and foot syndrome (HFS)/7, Hypertension/7, Diarrhoea/6, Anorexia/3, fatigue/9, Nausea/4, stomatitis/1, thrombocytopenia/2, anaemia/2 and toxic hepatitis/3; grade 3-4 was HFS/5, hypertension/1, thrombocytopenia/2 and fatigue/2. All PTS were valuable for response: 3 PTS (8.3%) had PR, 16 (44.4%) had SD and 16 had progression. Median TTP was 2.7 months (CI 95% 1.2-4.2) and Median OS was 7.4 months (CI 95% 5.6-9.1). CONCLUSIONS Based on our experience the combination of S ant LDPT is feasible and safe and has some activity against relapsed GBMs. The TTP of present study is comparable to the one obtained treating a similar subset of patients with bevacizumab (Zustovich et al. Anticancer Res. 2010; 12: 5213-6).

e14614 Background: There are no well-conducted randomized studies regarding the role of adjuvant chemotherapy for patients with radically resected biliary tract cancers and there is no standard accepted adjuvant treatment for these patients, even if the majority of them suffers from recurrent disease. Methods: We retrospectively reviewed the outcome of patients who underwent radical surgical resection for biliary tract cancer from 2005 to 2009 and who received adjuvant treatment or were followed up at our institution. The aim of our analysis was to evaluate the correlation between prognostic factors and disease-free survival (DFS) using Chi-square test and Cox regression analysis, and to explore the role of adjuvant treatment in these patients. The indication for adjuvant chemotherapy was based upon discussion of its role with every single patient. Results: Eighty-one evaluable patients, 44 (54%) women and 37 (46%) men, all ECOG performance status 0-1, were identified; median age was 67 years (range 30-81). The site of biliary cancer was intrahepatic in 19 patients, perihilar in 12, distal tree in 20, gallbladder in 11, ampullary carcinoma in 19 cases. Fifty-three patients (65%) had T3 or T4 tumors and 34 (42%) had positive nodes; 29 tumors (37%) were of grade 3-4; perineural or vascular invasion was present in 34 (42%) and 15 (19%) cases. Thirty-two (39%) patients received adjuvant chemotherapy with gemcitabine or fluoropyrimidines. On univariate analysis tumor extension, node status, grading, vascular invasion and adjuvant chemotherapy significantly correlated with DFS. In particular, patients with N1 tumour had a median DFS of 12.4 months versus 25.2 months of N0 patients. Patients who received adjuvant chemotherapy after surgery had a median DFS of 29.0 months compared to 17.5 months of patients treated with surgery alone (p=0.04). Multivariate analysis confirmed the negative prognostic role of lymph node involvement (p=0.04) and the positive impact of adjuvant chemotherapy (p=0.001). Conclusions: Adjuvant chemotherapy seems effective in prolonging DFS in radically resected biliary tract cancer patients. A phase III randomized trial should prospectively evaluate the role of adjuvant therapy.

Modern chemotherapy combinations for metastatic colorectal cancer (mCRC) comprise infusional 5-fluorouracil (5-FU), leucovorin, and irinotecan or oxaliplatin. The fluoropyrimidine derivative capecitabine is at least as effective as 5-FU plus leucovorin bolus regimens. It displays a favorable toxicity profile and offers the advantages of oral administration. The epidermal growth factor receptor antibody cetuximab induces synergistic antitumor activity when combined with chemotherapy. In pretreated patients, cetuximab can restore the sensitivity to irinotecan and, therefore, has been registered in this setting. Several phase I/II trials have investigated the combination of cetuximab with irinotecan-based or oxaliplatin-based chemotherapy for the first-line treatment of mCRC. These combinations have been proven to be safe and have provided promising efficacy data. A recent phase III trial confirmed improved progression-free survival, response rates, and a particularly significant increase of secondary resection rates for the combination of FOLFIRI (infusional 5-FU/leucovorin/irinotecan) plus cetuximab compared with FOLFIRI alone. In this review, we discuss the background of combining XELIRI (capecitabine/irinotecan) or XELOX (capecit-abine/oxaliplatin) with cetuximab for the first-line treatment of mCRC and present available data of these combined cytotoxic and targeted treatment approaches.

The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m −2 and oxaliplatin 85 mg m −2 on day 1 plus capecitabine 2000 mg m −2 per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3–4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response rate of 67% (95% CI 51.4–82%). After a median follow-up of 17.7 months, the median progression-free and overall survival were 10.1 and 17.9 months, respectively. The substitution of 5-fluorouracil with capecitabine, in combination with irinotecan and oxaliplatin, is feasible and does not impair the activity of the regimen. However, the XELOXIRI combination is associated with a high incidence of diarrhoea and, therefore, should be considered as a not preferable alternative to FOLFOXIRI.

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).

Purpose We aimed to investigate the prognostic significance of several baseline variables in stage IIIB-IV non-small cell lung cancer to create a model based on independent prognostic factors.Methods/Results A total of 320 patients were treated with last generation chemotherapy regimens. The majority of patients received treatment with cisplatin + gemcitabine or gemcitabine alone if older than 70 years or with an ECOG performance status (PS) = 2. Performance status of 2, squamous histology, number of metastatic sites > 2, presence of bone, brain, liver and contralateral lung metastases and elevated leukocyte count in peripheral blood were all statistically significant prognostic factors in univariate analyses whereas the other tested variables (sex, stage, age, presence of adrenal gland and skin metastases) were not. Subsequently, a multivariate Cox's regression analysis identified PS 2 (P < 0.001, hazard ratio 2.57), elevated leukocyte count (P < 0.001, hazard ratio 1.79), squamous histology (P = 0.005, hazard ratio 1.45) and presence of brain metastases (P = 0.035, hazard ratio 1.5) as independent prognostic factors for poor survival. Patients were assigned to one of three risk groups according to the cumulative risk defined as the sum of simplified risk scores of the four independent prognostic factors. Low-, intermediate- and high-risk patients achieved a median survival of 10.2 months (95% confidence interval (CI) 8.9-11.6), 5.1 months (95% CI 4.0-6.2) and 2.8 months (95% CI 0.5-5.2), respectively. The high-risk group encompassed PS 2 patients with two or three adjunctive unfavourable independent prognostic factors.Conclusions Performance status, white blood cells count, histology and brain metastases resulted in our series prognostic factors of survival in NSCLC patients treated with chemotherapy at a multivariate analysis. Leukocyte count resulted the stronger factor after performance status. If prospectly validated, the proposed prognostic model could be useful to stratify performance status 2 patients in specific future trials.

This multicenter phase II study evaluated, in chemonaive patients with stage IIIB–IV NSCLC, age ⩾70 and with a performance status 0–2, the activity, efficacy and tolerability of planned sequential administration of gemcitabine 1200 mg m−2 on days 1 and 8 every 3 weeks for three courses followed by three cycles of docetaxel 37.5 mg m−2 on days 1 and 8 every 3 weeks, provided there was no evidence of disease progression. A total of 56 patients entered the study. According to intention-to-treat analysis, the objective response rate was 16.0% (95% CI 7.6–28.3%); 23 patients (41.0%) had stable disease and 24 patients (43%) had progressive disease. Five patients who had a stable disease after three courses of gemcitabine obtained a conversion to partial response by docetaxel. Median time to progression was 4.8 months (95% CI 3.6–6.0 months) and median duration of survival was 8.0 months (95% CI 5.6–10.5 months). The 1-year survival rate was 34%. No grade 4 haematological toxicity was observed and grade 3 neutropenia and thrombocytopenia were reported in 5.4 and 3.6% of the patients, respectively. Grade 3/4 mucositis and grade 3 diarrhoea, both occurred in 3.6% of the patients and grade 3 asthenia was observed in 9% of patients. One patient reported a grade 4 skin toxicity. No treatment-related deaths occurred. Sequential gemcitabine and docetaxel is a well-tolerated and effective regimen in elderly advanced NSCLC patients.

4026 Background: As previously reported (ASCO 2006) the G.O.N.O. conduced a phase III study comparing FOLFIRI to FOLFOXIRI in 244 patients (pts) with not resectable MCRC. At a median follow-up of 18.4 months (mos) we reported significant improvements in response-rate (RR), R0 resection of metastases (mts), PFS and OS for FOLFOXIRI. Methods: Results have been updated (median follow-up of 36.2 mos) and 14 variables were tested as possible prognostic factors for response, R0 resection, PFS and OS. Results: At this updated analysis 225 (111 vs 114) pts have progressed and 180 (84 vs 96) have died. Results confirm the significant improvements for FOLFOXIRI in terms of confirmed RR (60% vs 34% p<0.001), R0 resection of residual mts (15% vs 6% p=0.033 and 36% vs 12% p=0.017 for pts with liver only mts), PFS (median 9.8 vs 6.9 mos p<0.001) and OS (median 23.6 vs 16.7 mos p=0.042) at the cost of a modest and acceptable increase in toxicity. In the logistic regression multivariate analysis treatment with FOLFOXIRI was the only independent predictive factor for response (HR:2.9, p<0.001) and for achieving an R0 surgical resection of mts (HR:3.1, p=0.018). The Cox’s multivariate analysis demonstrates that independent prognostic factors for improved time to progression were treatment with FOLFOXIRI (HR:0.64, p<0.001), and ECOG PS = 0 (HR:0.73, p=0.02) and for time to death were treatment with FOLFOXIRI (HR:0.74, p=0.04) and liver involvement <25% (HR:0.57, p=0.006). The benefits of FOLFOXIRI was consistent across all subgroups, including those with unfavorable prognosis such as pts with time from diagnosis to randomization <3 mos, multiple site of disease or liver involvement ≥ 25%. Conclusions: FOLFOXIRI confirms to be the first combination demonstrated to be superior to an infusional 5FU containing doublet as FOLFIRI in terms of RR, R0 resections, PFS and OS. FOLFOXIRI represents a new treatment option in MCRC and its use and study is of particular interest in a neoadjuvant strategy, in pts with few chances to achieve a three-drug exposure in a sequential strategy and in combination with targeted agents. Partially supported by Fondazione ARCO. No significant financial relationships to disclose.

GOLF is a triplet translational polychemotherapy regimen contaning gemcitabine, oxaliplatin, and 5-fluorouracil (plus levofolinic-acid); cytotoxic drugs currently used in the treatment of pancreatic carcinoma.It has shown promising anti-tumor effects in patients with different gastro-enteric malignancies, thus we carried out the present study to investigate its toxicity and anti-tumor activity also in patients with inoperable pancreatic carcinoma.Twenty-six patients were enrolled in the study, 15 males and 11 females with and average age of 61 years (range 31-81) and a performance status (ECOG) £ 3. Eight of them had already received a first-line chemotherapy, 15 had liver involvement and 11 had inoperable loco-regional disease.All patients received biweekly gemcitabine (1000 mg/m2 on day 1), Oxaliplatin (85 mg/m2 on day 2); levofolinic acid (100 mg/m2) and 5-FU (400 mg/m2 as a bolus, and 800 mg/m2 in 24 hour infusion) on days 1 and 2. We recorded a fatal event occurred just after the first cycle due to lung embolism; grade II-III-diarrhea and mucositis (48%); alopecia (40%); thrombocytopenia (20%); grade I-II asthenia, fatigue, non-neutropenic-fever (40%) and oxaliplatin-related neurotoxicity (20%).We also recorded an objective response and disease control rate of 32 % and 60 % (1 complete and 7 partial responses and 8 disease stabilizations) respectively, with clinical benefit and fast pain control in 60 % of the patients and with a median time to progression and overall survival of 5.5 and 8 months, respectively.In conclusion, GOLF regimen appears to be a feasible treatment for patients with pancreatic carcinoma that deserves to be evaluated in phase III trial.

13111 Background: Preclinical studies have demonstrated that the frequent administration of low doses of cytotoxic drugs over prolonged periods of time (MC) reduces tumour cell growth through inhibition of angiogenesis. The antitumor effect of a MC with cyclophosphamide is due to an increase of thrombospondin-1 (TSP-1) plasma level, an endogenous inhibitor of angiogenesis. Methods: An exploratory study was conducted to assess the feasibility, the activity and the optimal metronomic dose of CPT-11 when administered as protracted continuous infusion (c.i.) in pretreated MCRC. A pharmacodynamic evaluation of anti- and pro-angiogenic factors, such as TSP-1 and vascular endothelial growth factor (VEGF), was performed. Weekly blood samples were taken. Three different CPT-11 dose levels have been evaluated: 1.4, 2.8 and 4.2 mg/sqm/day; 25%, 50% and 75% of the maximum CPT-11 tolerated dose in c.i. (5.6 mg/sqm/day), respectively. Results: Between Apr 04 and May 05 20 patients have been enrolled. Patients characteristics were: M/F = 11/9, median age = 71 years (range 51–79); PS 0/1/2 = 8/11/1; sites of metastasis: single/multiple = 7/13; median of previous lines of chemotherapy: 3 (range 1–5). No toxicities of grade >1 NCI scale have been observed. No objective responses were observed, but 4 patients (20%) had a stable disease with a median duration of 14 weeks (range 11–20). TSP-1 plasma levels significantly increased after one week and remained higher than the baseline for more than 8 weeks (120.1±10.3% vs. 100% of day 0). VEGF levels did not significantly change during the CPT-11 infusion. No statistical differences have been found for TSP-1 and VEGF concentrations among the three dose levels. Conclusions: CPT-11 metronomic chemotherapy is feasible. Plasma TSP-1 markedly increased during metronomic CPT-11 administration, suggesting a modulation of the angiogenic process in cancer patients. Supported by A.I.R.C. [Table: see text]

4074 Background: Prognosis of pts with initially unresectable MCRC can be improved if chemotherapy induces a significant down- sizing of disease thus allowing an R0 surgical resection of mts. The activity of the regimen used is correlated with the rate of R0 resections and the GONO-FOLFOXIRI improved the rate of R0 resection over FOLFIRI (Falcone, JCO’07). The objective of this analysis is to evaluate whether the increase in the rate of resection is also associated with a favorable outcome in the long term. Methods: Overall 196 pts with initially unresectable MCRC and not selected for a neo-adjuvant strategy were treated with FOLFOXIRI (irinotecan 165 mg/sqm d1, oxaliplatin 85 mg/sqm d1, l-LV 200 mg/sqm d1, 5FU 3200 mg/sqm 48-h continuous infusion starting on d1, repeated every 2 weeks) in phase II and III trials. This regimen was associated with an elevated activity (ORR: 66%-72%) and 37 patients (19%) could undergo to a secondary R0 surgery on mts. Results: Characteristics of the 37 radically resected pts were: median age 64 years (45–73), ECOG PS ≥1: 30%, median CEA: 10 ng/ml (1–288), liver involvement ≥ 25%: 43%. Sites of disease were liver only: 68%, lung only: 11%, liver + lymphnodes: 13%, liver + peritoneum: 3%, liver + lung: 5%. Mts were synchronous in 68% of pts. Pre-operative FOLFOXIRI was administered for a median of 11 cycles (3–15). There was no perioperative mortality. After a median follow up of 61 mos median OS is 41+ mos, 5-year and 8-year survival are 45% and 33% respectively. In 11 pts (36%) progressed after surgery a surgical re-resection and/or radiofrequency ablation was performed. Up today 29% of pts are free of disease. The analysis of treatment-induced liver injury (so far performed on 17 patients) has not shown nor steato-hepatitis, nor G3 steatosis, nor G3 vascular toxicity. Conclusions: The GONO-FOLFOXIRI not only improves the rate of R0 surgery in unresectable MCRC pts, but also survival of resected pts is considerable and compares well to that achieved with other regimens. Furthermore neoadjuvant FOLFOXIRI for 3–6 months is safe and not associated with unexpected adverse events or severe liver injury. Supported by Fondazione ARCO. No significant financial relationships to disclose.

Sequential chemotherapy may improve treatment efficacy avoiding the additive toxicity associated with concomitant polichemotherapy in hormone-refractory prostate cancer (HRPC). Forty patients received docetaxel 30 mg m−2 intravenous (i.v.), weekly, plus estramustine 280 mg twice daily for 12 weeks. After 2 weeks rest, patients with a decline or stable PSA were treated with mitoxantrone 12 mg m−2 i.v. every 3 weeks plus prednisone 5 mg twice daily for 12 cycles. Forty patients were assessable for toxicity after docetaxel/estramustine. Main toxicities were grade 3–4 AST/ALT or bilirubin increase in seven patients (17.5%) and deep venous thrombosis (DVT) in four patients (10%). Twenty-seven patients received mitoxantrone/prednisone. Main toxicities included DVT in one patient (3.7%) and congestive heart failure in two patients (7%). Thirty-nine patients were assessable for PSA response. Twenty-nine patients (72.5%; 95% CI 63–82%) obtained a ⩾50% PSA decline with 15 patients (37.5%; 95% CI 20–50%) that demonstrated a ⩾90% decrease. Median progression-free and overall survival were respectively 7.0 (95% CI 5.8–8.2 months) and 19.2 months (95% CI 13.9–24.3 months). In conclusion, although this regimen demonstrated a favourable toxicity profile, sequential administration of mitoxantrone is not able to improve docetaxel activity in patients with HRPC.