Bolus 5FU Research Articles

Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Cost-Effectiveness Analysis of Capecitabine Compared with Bolus 5-Fluorouracil/l-Leucovorin for the Adjuvant Treatment of Colon Cancer in Japan

A cost-effectiveness analysis of oral capecitabine versus intravenous bolus 5-fluorouracil/l-leucovorin (FU/LV) as adjuvant therapy in patients with stage 3 colon cancer was performed from a Japanese healthcare payer perspective. Adjuvant therapy comprised 24 weeks of treatment with either oral capecitabine 1250 mg/m(2) twice daily on days 1-14 of a 21-day cycle or intravenous bolus FU 500 mg/m(2) and LV 250 mg/m(2) weekly for 6 weeks of an 8-week cycle (Roswell Park regimen). The analysis comprised short-term (1 year after initiation of adjuvant therapy) and long-term (up to 15 years) components. The long-term analysis involved a three-state (disease-free, recurrence and death) Markov model. Estimates for transition probabilities, costs and utilities were derived from the X-ACT trial, a Japanese phase II trial, and other published sources. Cost estimates were considered from the perspective of a healthcare payer. Costs were expressed in Japanese Yen (yen), year 2007 values. A discount rate of 3% was applied to costs and outcomes. Cost effectiveness was expressed as a cost per QALY. The effects of uncertainty were explored through one-way and probabilistic sensitivity analyses. In the 1-year analysis, direct costs were yen440,000 ($US4000) less per patient with capecitabine than with FU/LV. In the long-term analysis, differences between treatments in direct medical costs ranged from yen470,000 ($US4300) to yen580,000 ($US5300) depending on the time horizon used. Capecitabine was also projected to increase the number of QALYs compared with FU/LV. The sensitivity analysis suggested that the model outcome was robust. The probabilistic sensitivity analysis estimate of capecitabine being the dominant regimen was 96.6% at a zero willingness to pay. Direct costs remained lower with capecitabine if the price of generic LV was >OR=50% of the branded product. This analysis suggests that capecitabine improves health outcomes and lowers direct costs compared with bolus FU/LV (i.e. dominant treatment strategy) when used as adjuvant therapy in patients with stage 3 colon cancer in Japan.

Oral fluoropyrimidines versus 5-fluorouracil for colorectal cancer: Results of a systematic review and meta-analysis

4111 Background: Previous studies showed that continuous intravenous infusion (cIV) of 5-fluorouracil (5FU) is associated with best tumor response in comparison to bolus 5-FU and perhaps, a slight increase of overall survival. There are some non-inferiority trials comparing oral fluoropyrimidines with bolus or cIV of 5FU, but there is still no definitive evidence of equivalence. This systematic review evaluated the efficacy of oral fluoropyrimidines compared to bolus or cIV administration of 5FU in colorectal cancer. Methods: PubMed, EMBASE, CENTRAL and LILACS databases were searched. Eligible studies were randomized trials (RCTs) comparing chemotherapy regimens containing oral fluoropyrimidines (capecitabine, UFT or Tegafur) and 5FU (bolus or cIV) in patients with colorectal cancer. The primary outcome was overall survival (OS). Secondary outcomes included response rate (RR), progression-free survival (PFS) and disease-free-survival (DFS). Hazard Ratio (HR) and Odds Ratio (OR) with fixed effect model were used for meta- analysis and were expressed with 95% confidence intervals (CI). Results: We included results from 20 RCTs, with a total of 14,779 patients. Compared to cIV of 5FU, capecitabine resulted in lower RR (OR 0.82; 95% CI 0.72 to 0.95; p=0.006), shorter PFS (HR 1.09; 95% CI 1.01 to 1.17; p=0.02) and was associated with a non- significant reduction in OS (HR 1.05; 95%CI 0.97 to 1.14; p=0.23). Compared to bolus 5FU, capecitabine resulted in lower RR (OR 0.80; 95% CI 0.65 to 0.98; p=0.004), but similar OS and PFS. Compared to bolus 5FU, the use of other fluoropyrimidines resulted in similar RR, OS and PFS. Conclusions: Oral fluoropyrimidines are equivalent to bolus 5FU in terms of efficacy, but provides less benefit than cIV 5FU. Combination chemotherapy with cIV 5FU remains the first choice for patients with colorectal cancer. [Table: see text]

Utility of concomitant chemoradiotherapy with 5-fluorouracil (5-FU) single agent as neoadjuvant treatment regimen in mexican patients with stage III rectal cancer: Experience in the Oncology Hospital

e15144 Background: To analyze overall survival, free disease survival, complete and partial pathologic response, effect of stage reduction, toxicity profile and number of anus preservative surgery in patients treated with concurrent chemo radiotherapy with a modified 5-FU single agent regimen as neoadjuvant modality treatment. Methods: Historic Cohort of patients treated in the Oncology Hospital, CMNSXXI between January 1999 to December 2004. The scheme used was a bolus of 5FU 425mg/m2 without leocovorin in three consecutive days each two weeks (days 1–3, 15 -17 and 29–31). Results and Conclusions: There were identified 96 consecutive patients with clinical stage III. The median age was 57.5 years. Ninety and two patients were operated and 51% was candidates to conservative surgery. There were 12.5% of complete pathologic responses and 35% of partial responses. The median of survival has not been reached. The five years of overall survival was 62% and the five-years of disease free survival was 55%. Stage reduction had impact in overall survival with 65% vs 40% at 9.5 years of follow up, and DFS was 58% vs 48% at 9.5 years. We report 16 cases of gastrointestinal toxicity grade 3 and two cases with grade 4. There was reported fourth cases of afebril neutropenia grade 4. Results in OS, DFS and number of complete pathological response were similar to reported by another oncology groups. Stage reduction was traduced in an increased of OS. This schedule can be feasible and applicable in another institutions in develop countries. No significant financial relationships to disclose.

Phase II trial of chemotherapy with high-dose FOLFIRI plus bevacizumab in the front-line treatment of patients with metastatic colorectal cancer (mCRC) and genotype UGT1A1*1/ UGT1A1*1 or UGT1A1*1/ UGT1A1*28 (FFCD 0504 trial). Results of a planned interim analysis

4065 Background: The antitumor efficacy of irinotecan may be dose dependent. In a recent phase II trial, the combination of high-dose irinotecan (260 mg/m2) with LV5FU2 regimen was feasible with an acceptable safety profile and promising efficacy data (Ducreux et al. Oncology 2008;74:17–24). The aim of this study was to evaluate the association of the high-dose FOLFIRI plus bevacizumab in patients (pts) selected on the UGT1A1 polymorphism, which could be predictive of the irinotecan toxicity. Methods: Pts with UGT1A1 *1/*1 (group 1) or *1/*28 (group 2) genotypes and previously untreated mCRC were treated with bevacizumab 5 mg/kg D1, irinotecan 260 mg/m2 D1, LV 400 mg/m2 D1, 5FU 400 mg/m2 IV bolus D1 and 5FU 2400 mg/m2 46h infusion D1–2 every 2 weeks. Using Bryant & Day design with OR (independent review, H0 ≤ 40%; H1 : ≥ 60%) and toxicity (gr 4 neutropenia or febrile neutropenia or gr3–4 diarrhea; H0 ≥ 20%; H1≤ 5% ) as primary endpoints; a total of 108 pts, 54 in each group, was required (alpha 5% and power 80%) with a planned interim analysis after the inclusion of 17 pts by group. The trial will be stopped at interim analysis if ≤ 7 pts had an OR and/or ≥ 3 pts had a severe toxicity. All analyses were performed in ITT. Results: At the time of interim analysis, done for group 1 when the 17th pt had a 6-months follow-up, 96 pts have been included (group 1: 40 pts, group 2: 46 pts). An objective response rate was observed in 9/17 pts but 7/17 pts had a severe toxicity (gr 4 neutropenia: 2 pts, febrile neutropenia: 2 pts, gr 3 diarrhea: 4 pts). Overall, 14/17 pts had a gr3–4 toxicity. There was no toxic death. According to interim analysis rules, the trial was closed to inclusion (for both groups) on December 16th 2008 for toxicity. The interim analysis for pts of group 2 is planned for February 2009 when the 17th patient will have a 6-months follow- up. Conclusions: High-dose FOLFIRI plus bevacizumab, although effective, was associated with a high toxicity rate among pts with UGT1A1 *1/*1 genotype. Complete tolerance, efficacy and survival results for all included patients will be presented at the meeting. [Table: see text]

Postoperative LV5FU2 combination chemotherapy in patients with curative resected advanced gastric cancer

e15660 Background: To illuminate the effect and toxicity of fortnightly low-dose leucovorin(LV) and fluorouracil(5FU) bolus plus continuous infusion(LV5FU2) postoperative chemotherapy(adjuvant) in patients with curative resected, advanced gastric cancer. Methods: Total 40 patients were enrolled in this study. All patients received LV 20mg/m2(bolus), 5FU 400mg/m2(bolus), 5FU 600mg/m2(24-hour continuous infusion) on day 1, 2, 15, and 16, every 4 weeks(LV5FU2), total 6 cycles. Results: Postoperative chemotherapy was initiated median 19 days after surgery. Total of 238 cycles were administered and median follow-up was 602 days. The median disease-free survival time was 728 days (95% CI, 411∼1045) and 2-year overall survival was 77%. Relapses were reported in 18 (45%) of the patients : Two of 9 patients relapsed in stage IIIA (22.2%), seven of 12 patients relapsed in stage IIIB (58.3%) and nine of 17 patients relapsed in stage IV (52.9%). They were all distant relapsed. Eight patients died. 7 patients died as a result of cancer progression and 1 patient suicided while receiving palliative chemotheraphy for cancer relapse. The grade 3∼4 toxicity of neutropenia 8.4% and anemia 0.4%, neutropenic fever 0.4% were observed. Conclusions: Postoperative LV5FU2 adjuvant chemotherapy is effective and tolerable for the patients with curative resected, advanced gastric cancer. No significant financial relationships to disclose.

Comparison of l and dl forms of folinic acid in Gercor C96.1 trial (A phase III trial comparing bimonthly LV5FU2 to monthly high-dose 5FU-leucovorin in patients with Dukes’ B2 and C colon cancer)

e15004 In C96.1 study (André T et al; J Clin Oncol. 2007 20;25:3732–8), patients were randomized to either monthly 5FU-LV hd (dl LV 200 mg/m2 or l LV 100 mg/m2 15 min iv followed by 5FU 400 mg/m2 15 min iv, d1–5 q4 wk) or LV5FU2 (dl LV 200 mg/m2 or l LV 100 mg/m2 2-hour infusion followed by iv bolus 5FU 400 mg/m2 and 22 hours continuous infusion 600 mg/m2, d1 and d2 q 2 wk). Form l LV was administered to 60% (n=519) of patients and dl LV to 40% (n=357) of patients. It was unknown in 29 patients. No randomization was made between form l or dl (It was the choice of each center). The aim of this analysis was to compare the 2 LV forms in term of safety and efficacy. Important prognostic characteristics were well balanced between the 2 groups. The proportion of any grade III-IV toxicity was 20% in l form and 17% in dl form. There was no difference in term of toxicity between the two groups, except a trend for more diarrhea grade 3–4 in form l (8% in l form vs 4% in dl form, p=0.07). The median follow-up time was 6.2 years in l form and 6.0 years in dl form. There were no statistically significant differences between l and dl forms in term of disease free survival (33.3% vs 32.8% of patients with at least one event in l and dl forms respectively, hazard ratio=1.03, 95% CI=[0.82–1.31], p=0.78). In term of overall survival, there was a trend without statistical significance in favor of l form (21.8% vs 25.5% of patients who died, hazard ratio=1.28, 95% CI=[0.97–1.69], p=0.078). We conclude that the toxicity profile is similar between the two forms (excepted diarrhea). The difference in overall survival should not be attributed to folinic acid form as no difference was observed on DFS. No significant financial relationships to disclose.

A phase II (PhII) trial of sorafenib (S) in combination with 5-fluorouracil (5FU) continuous infusion (c.i.) in patients (pts) with advanced hepatocellular carcinoma (HCC): Preliminary data

4592 Background: S, an oral multi-kinase inhibitor that targets Raf-kinase and receptor tyrosine kinases, improved overall survival (OS) and time to progression (TTP) versus placebo in a randomized phase III study in HCC (SHARP study). The safety of S in association with infusional and bolus 5FU regimens was established in a previous PhI study, with no clinically relevant pharmacokinetic interaction between S and 5FU. The present trial was designed to evaluate the safety and efficacy of S with infusional 5FU in HCC pts. Methods: Patients with advanced HCC (not eligible to surgical or locoregional therapies), age≥18 years, Child-Pugh Class A or B, ECOG PS 0–1, without prior systemic treatment for HCC and adequate bone marrow, liver and renal function, were eligible for the study. The primary endpoint is the Disease Control Rate (DCR). Secondary endpoints included response rate, TTP, OS and safety. According to a two-step Simon's model 46 pts were to be accrued. Pts were treated with oral S 400 mg bid continuously and c.i. 5FU 200 mg/sqm/day day 1–14 every 3 weeks. Tumour response was assessed according to RECIST criteria every 9 weeks. Results: Between October 2006 and October 2008 38 pts were enrolled: M-F: 32–6, median age (range): 68(47–83) years, ECOG-PS 0–1: 28–10, Child-Pugh A-B: 35–3, extrahepatic spread: 14 pts, macroscopic vascular invasion: 6 pts. Grade 3/4 (%) toxicities (NCI CTC v 3.0 criteria) included diarrhoea 5/0, stomatitis 21/3, hand foot syndrome 21/0, skin rash 11/0, hypertension 11/0; hyperbilirubinemia 5/3, AST 11/0, ALT 8/0, cardiac toxicity (one cardiac failure, one atrial fibrillation) 5/0 and bleeding (melena) in 3/0. One partial response was observed. Stable disease was obtained in 45% of pts with a median duration of 9.6 months (range 5–18+). Median TTP was 7.6 months (CI 95%=5.3–9.9) and median OS 12.2 months (CI 95%=4.45–19.8). Conclusions: Preliminary results of this PhII study show encouraging disease control rate, TTP and OS in pts with advanced HCC. The S+5FU association is feasible, well tolerated and AEs were predictable and manageable. [Table: see text]

Rectal cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Rectal cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up B. Glimelius & J. Oliveira On behalf of the ESMO Guidelines Working Group* Department of Oncology, Radiology and Clinical Immunology, University Hospital, Uppsala and Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden; Service of Medical Oncology, Portuguese Institute of Oncology, Lisbon, Portugal

A phase I study of an oral simulated FOLFOX with high dose capecitabine

A phase I study of high-dose capecitabine given over 2 days, along with oxaliplatin, bolus 5FU and leucovorin (LV), was designed to simulate FOLFOX6 without the need for infusional 5FU. Schedule A included oxaliplatin 100 mg/m(2), 5FU 400 mg/m(2), and LV 20 mg/m(2) (all given IV on days 1 and 15, 28 day cycle). Capecitabine was administered orally every 8 h x 6 doses, days 1 and 15. Schedule B excluded 5FU and LV, maintaining oxaliplatin and capecitabine. Pharmacokinetics were performed for capecitabine for 6 patients on each schedule. 36 patients were treated. The dose-limiting toxicities seen included nausea, dehydration, fatigue, hypotension and confusion. Minimal palmar-plantar erythrodysesthesia was seen. Myelosuppression was common, but not a dose limiting toxicity. The pharmacokinetic parameters for capecitabine were unaltered. Using capecitabine to mimic FOLFOX6 is feasible and well tolerated with a toxicity profile that differs from standard 14-day capecitabine dosing, with less palmar-plantar erythrodysesthesia. The phase II dose for capecitabine in combination with oxaliplatin, 5FU, and LV is 1,500 mg/m(2)/dose or 2,250 mg/m(2)/dose in the absence of bolus 5FU/LV.

Phase I trial of oxaliplatin with fluorouracil, folinic acid and concurrent radiotherapy for oesophageal cancer

This dose escalation study was designed to determine the maximum tolerated dose (MTD) and recommended doses (RDs) of 5-fluorouracil (5FU), folinic acid and oxaliplatin (FOLFOX) with concomitant radiotherapy in inoperable/metastatic oesophageal squamous cell carcinoma or adenocarcinoma. Patients received three courses of LV5FU2 regimen (folinic acid 200 mg m−2, bolus 5FU 300–400 mg/m2, continuous infusion 5FU 400–600 mg m−2 on days 1 and 2) and escalating doses of oxaliplatin 50 to 100 mg m−2 on day 1 (FOLFOX). This regimen was repeated every 2 weeks, concomitant to a 50-gray radiotherapy per 5 weeks. Three more cycles were delivered after completion of radiation therapy. Three to six patients were allocated to each of the five dose levels until MTD was reached. Thirty-three patients were enroled and 21 had metastatic disease. Maximum tolerated dose was oxaliplatin 100 mg m−2, and continuous infusion 5FU was 600 mg m−2 day− (level 5). The most common toxicities were neutropenia, dysphagia and oesophagitis. The RDs were those of FOLFOX-4 regimen (oxaliplatin 85 mg m−2 and full doses of LV5FU2). The overall response was 48.5%, including 12% complete response. Response rate on primary tumour was 62.9%. This FOLFOX-4 regimen was reasonably well tolerated and effective in inoperable/metastatic oesophageal carcinoma and warrants additional investigation.

Adjuvant Chemotherapy After Potentially Curative Resection of Metastases From Colorectal Cancer: A Pooled Analysis of Two Randomized Trials

Adjuvant systemic chemotherapy administered after surgical resection of colorectal cancer metastases may reduce the risk of recurrence and improve survival, but its benefit has never been demonstrated. Two phase III trials (Fédération Francophone de Cancérologie Digestive [FFCD] Trial 9002 and the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Clinical Trials Group/Gruppo Italiano di Valutazione Interventi in Oncologia [ENG] trial) used a similar design and showed a trend favoring adjuvant chemotherapy, but both had to close prematurely because of slow accrual, thus lacking the statistical power to demonstrate the predefined difference in survival. We report here a pooled analysis based on individual data from these two trials. After complete resection of colorectal liver or lung metastases, patients were randomly assigned to chemotherapy (CT arm; fluorouracil [FU] 400 mg/m(2) administered intravenously [IV] once daily plus dl-leucovorin 200 mg/m(2) [FFCD] x 5 days or FU 370 mg/m(2) plus l-leucovorin 100 mg/m(2) IV x 5 days [ENG] for six cycles at 28-day intervals) or to surgery alone (S arm). A total of 278 patients (CT, n = 138; S, n = 140) were included in the pooled analysis. Median progression-free survival was 27.9 months in the CT arm as compared with 18.8 months in the S arm (hazard ratio = 1.32; 95% CI, 1.00 to 1.76; P = .058). Median overall survival was 62.2 months in the CT arm compared with 47.3 months in the S arm (hazard ratio = 1.32; 95% CI, 0.95 to 1.82; P = .095). Adjuvant chemotherapy was independently associated with both progression-free survival and overall survival in multivariable analysis. This pooled analysis shows a marginal statistical significance in favor of adjuvant chemotherapy with an FU bolus-based regimen after complete resection of colorectal cancer metastases.

Safety and Efficacy of Oxaliplatin and Fluoropyrimidine Regimens With or Without Bevacizumab As First-Line Treatment of Metastatic Colorectal Cancer: Results of the TREE Study

To evaluate the safety and efficacy of three oxaliplatin and fluoropyrimidine regimens, with or without bevacizumab, as first-line treatment for metastatic colorectal cancer (CRC). Patients with histologically documented metastatic or recurrent CRC and no prior treatment for advanced disease were randomly assigned to mFOLFOX6 (bolus and infusion fluorouracil [FU] and leucovorin [LV] with oxaliplatin), bFOL (bolus FU and low-dose LV with oxaliplatin), or CapeOx (capecitabine with oxaliplatin), respectively (Three Regimens of Eloxatin Evaluation [TREE-1]). The study was later modified such that subsequent patients were randomized to the same regimens plus bevacizumab (TREE-2). A total of 150 and 223 patients were randomly assigned in the TREE-1 and TREE-2 cohorts, respectively. Incidence of grade 3/4 treatment-related adverse events during the first 12 weeks of treatment were 59%, 36%, and 67% for mFOLFOX6, bFOL, and CapeOx, respectively, (TREE-1) and 59%, 51%, and 56% for the corresponding treatments plus bevacizumab (TREE-2; primary end point). CapeOx toxicity in TREE-1 included grade 3/4 diarrhea (31%) and dehydration (27%); capecitabine dose reduction to 1,700 mg/m(2)/d in TREE-2 resulted in improved tolerance. Overall response rates were 41%, 20%, and 27% (TREE-1) and 52%, 39%, and 46% (TREE-2); median overall survival (OS) was 19.2, 17.9, and 17.2 months (TREE-1) and 26.1, 20.4, and 24.6 months (TREE-2). For all treated patients, median OS was 18.2 months (95% CI, 14.5 to 21.6; TREE-1) and 23.7 months (95% CI, 21.3 to 26.8; TREE-2). The addition of bevacizumab to oxaliplatin and fluoropyrimidine regimens is well tolerated as first-line treatment of mCRC and does not markedly change overall toxicity. CapeOx tolerability and efficacy is improved with reduced-dose capecitabine. First-line oxaliplatin and fluoropyrimidine-based therapy plus bevacizumab resulted in a median OS of approximately 2 years.

A randomised phase III trial of adjuvant radio-chemotherapy comparing Irinotecan, 5FU and Leucovorin to 5FU and Leucovorin in patients with rectal cancer: A Hellenic Cooperative Oncology Group Study

The primary objective was to compare the 3-year survival of rectal cancer patients randomised postoperatively to irinotecan (IRI), Leucovorin (LV) and bolus 5-fluorouracil (5FU) or LV-bolus 5FU with radiotherapy. Secondary objectives included disease-free survival, local relapse and toxicity.The study included 321 eligible patients. The treatment consisted of weekly administration of IRI 80mg/m2 intravenously (IV), LV 200mg/m2 and 5FU 450mg/m2 bolus (arm A) versus LV 200mg/m2 and 5FU 450mg/m2 IV bolus (arm B). One cycle included four infusions and treatment was continued for a total of six cycles. The first cycle was followed by pelvic irradiation plus 5FU.There were no differences between the arms in 3-year overall, disease-free and local relapse-free survival. Grades 3 and 4 toxicity was similar in both the arms with the exception of leucopaenia, neutropaenia and alopecia, which were higher in the IRI arm.IRI added to adjuvant radiochemotherapy with LV and bolus 5FU was not shown to improve survival, whereas the incidence of severe leucopaenia was significantly higher in the IRI arm.

A phase II study of an adapted CT with oxaliplatin (Oxa) and bolus 5FU in I-line treatment of metastatic CRC in elderly patients not eligible to FOLFOX

15124 Background: FOLFOX and FOLFIRI have been established to be an effective I-line CT for mCRC. Not all over 70-yrs old pts can receive infusional 5-FU because of cardiac comorbidity, refuse of infusional CT or vulnerability state at the comprehensive geriatric assessment (CGA). Till now no alternative schedules containing Oxa have been assessed in elderly pts. The aim of the present study was to evaluate the feasibility and activity of biweekly Oxa plus bolus 5FU and low dose LV as I-line CT. Methods: pts ≥70 yrs with measurable, chemonaive mCRC, ECOG PS ≤2, not eligible to infusional 5FU, fit or vulnerable at CGA (Balducci et al) received Oxa 85 mg/m2 on d 1 and 15, LV 20 mg/m2 plus bolus 5FU 500 mg/m2 on d 1, 8 and 15 every 28d. Study design was 1 stage, estimated sample size 34. Toxicity was the primary endpoint. Response was evaluated by CT-scan every 2 cy. Results: 35 pts, median age 74 (range 70–84) entered the study. Ten pts (28.6%) had cardiological comorbidities. Median number of comorbidities was 1.3 among 20 vulnerable pts, 0 among 15 fit pts. Toxicity according to CTC v 3.0 (see table), was not related to age or CGA. 46.7% of fit pts and 70% of vulnerable pts received < 6 cycles of CT because of toxicity (7 pts), PD (6 pts) or refuse (8 pts). Out of 28 valuable pts 10 PR were observed for an RR of 35.7% (95% CI 17.9–53.4%). Eleven pts had SD (39.3%) while 7 progressed during treatment (25%). After a median follow up of 29.3 mo 32 pts progressed or died, with a median PFS of 9.4 mo. Totally 24 out of 35 pts died, for a median OS of 16.3 mo. A clinical difference in terms of OS among 15 pts receiving II line CT and the other 20 receiving only best supportive care (13.9 vs 11.4, p=0.19 n.s.) was reported. Conclusions: Biweekly Oxa with bolus 5-FU is a safe and effective alternative in elderly pts not susceptible to FOLFOX because of refuse by pts or vulnerability at CGA. Toxicity Toxicities Grade 2 Grade 3 Grade 4 Number % Number % Number % Anemia 4 11.4 1 2.8 0 0 Neutropenia 3 8.6 3 8.6 1 2.8 Trombocytopenia 3 8.6 0 0 0 0 Diarrhea 2 5.7 5 14.3 1 2.8 Mucositis 2 5.7 0 0 1 2.8 Vomiting 2 5.7 1 2.8 0 0 Neurotoxicity 6 17.1 3 8.6 1 2.8 Fatigue 3 8.6 1 2.8 0 0 No significant financial relationships to disclose.

Folfiri-bevacizumab as first line treatment for advanced colorectal cancer (ACRC): Results from 77 consecutive unsellected patients

15056 Background: Bevazicumab (BV) combined with IFL (Irinotecan, bolus 5FU and Leucovorin) improves response rate (ORR) and overall survival (OS) in patients (p) with ACRC. Nowadays, infusional 5FU based combinations are considered the optimal schedules. In EU, only irinotecan based combinations are approved for the use in combination with B in the first line setting. We analysed the efficacy and toxicity of a consecutive cohort of unselected patients with ACRC treated with FOLFIRI-BV. Methods: From Aug-05 to Mar-07, 77p with unresectable ACRC received BV 5mg/kg d1, Irinotecan 180mg/m2 d1, Leucovorin 200mg/m2 d1 y 2, 5FU 400mg/m2 bolus and 600mg/m2 CI of 22h d1 and 2, every 14 days (FOLFIRI-BV). There were 50 males and the median age was 63 y (29–83). ECOG 0/1/2: 34/40/3. Primary tumor: colon 43p, rectum 33p, 1p doble primary. Median number of metastatic sites was 1.5 (1–4). According to Khone risk classification, there were 60% of low risk patients, 35% of intermediate rist and 5% of high risk. Results:...

LV5FU2-cisplatin followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: Preliminary results of a randomized phase III trial (FFCD 0301)

4513 Background: Pts with metastatic pancreatic adenocarcinoma (MPA) have a poor prognosis with no major survival improvement since the introduction of gemcitabine (Burris 1997). The LV5FU2-P regimen was reported as safe and active with a 9 months median overall survival (OS) in a phase II trial (Taïeb 2002). This randomized multicenter phase III trial compared LV5FU2-P followed by gemcitabine in arm A versus gemcitabine followed by LV5FU2-P in arm B to evaluate the best sequence. Methods: Pts with measurable MPA, PS 0–2, non prior CT, were randomly assigned to receive either LV5FU2-P (2-hour infusion of LV 200 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 mg/m2 every 2 weeks, with cisplatin 50 mg/m2 as a 2-hour infusion on D1 or 2, followed by gemcitabine (1,000 mg/m2 for 7 weeks out of 8 and then 3 weeks out of 4) at progression or toxicity (arm A) or the opposite sequence (arm B). Randomization was done using minimization with stratification according to center, PS tumoral localization and infusion duration. Primary endpoint was OS. It was required to include 202 pts and observe 170 deaths to detect an expected improvement in median OS from 6.5 to 10 months in arm A (bilateral α = 5% and β = 20%). Secondary endpoints included progression free-survival (PFS) after first and second line, toxicity, quality of life (QLQ-C30) and percentage of second line in each arm. Results: From 08/2003 to 05/2006, 202 pts were included in 33 centers, 102 in arm A and 100 in arm B. Median age (62 [40 - 84] vs 64 [39 - 81] years), male/female ratio (1.7 vs 1.7), PS 0–1 (76.5% vs 83%), previous surgery (22.5% vs 27%). After a median follow-up of 33,6 months [min 17; max 48], 185 pts had died. Median OS for arm A was 6.6 months [95% CI- 5.2 to 8.4] versus 8.2 months [95% CI- 6.1 to 9.7] for arm B (HR B vs A 0.95 [95% CI 0.71 - 1.27], Log Rank p = 0.72). 1- year and 2-year survival rates were 29.5% and 8% for arm A versus 34.5% and 3.5% for arm B, respectively. Conclusions: This trial failed to reach its primary endpoint and both sequences achieved a similar efficacy with no significant differences between the two arms in median OS. Updated results (including response, PFS and toxicity analyses) will be presented at the meeting. No significant financial relationships to disclose.

A retrospective comparison of concurrent bolus 5-fluorouracil or raltitrexed in preoperative chemoradiation for locally advanced rectal cancer

5-fluorouracil (FU) is commonly used in preoperative chemoradiation in locally advanced rectal cancer, but not all patients cooperate in taking the 5-day continuous infusion regimen. Raltitrexed (RA), a thymidylate synthase inhibitor, is one of the agents used in place of FU in such cases. We retrospectively compared the toxicity, tumor downstaging, pathologic response and relapse rate with bolus FU or RA during concurrent radiotherapy (RT) to assess the role of RA in place of FU. We conducted a retrospective analysis of response rates and toxicity data on 59 patients diagnosed with locally advanced rectal cancer and treated with surgery following preoperative chemoradiation with either concurrent FU or RA between January 1999 and December 2004. Median follow-up was 38 months (range, 1-70). Ten patients (10%) had grade 3 gastrointestinal (GIS) toxicity during chemoradiation. The pathologic complete response rates were 6% with FU and 7% with RA (P = 0.844), while 66.7% of patients treated with FU and 37.1% with RA had downstaging of the T stage after chemoradiation (P = 0.026). The sphincter preservation rates were 45.8% with FU and 51.4% with RA (P = 0.912). The 5-year local control rates were 79.2% for patients treated with RT+FU and 85.76% for patients treated with RT+RA (P = 0.510). Compared with the RT+RA regimen, the incidence of downstaging was greater with RT+FU, but RT+FU was associated with a correspondingly greater rate of acute grade 2 GIS toxicity. However, no significant differences were seen in sphincter preservation, pathologic complete response, local control and distant recurrences rates among patients. FU seems to be the best therapeutic choice, while RA seems to be as effective as bolus FU.

Capecitabine, Alone and in Combination, in the Management of Patients with Colorectal Cancer

Capecitabine, an oral prodrug of fluorouracil (5FU), has shown efficacy in terms of progression-free and overall survival at least equivalent to standard folinic acid (leucovorin)-modulated intravenous 5FU bolus regimens in patients with metastatic colorectal cancer. Moreover, capecitabine has demonstrated a better tolerability profile, producing a significantly lower occurrence of severe stomatitis than 5FU plus folinic acid regimens, making this drug particularly attractive for treating elderly patients. In addition, capecitabine can be combined with other active drugs such as irinotecan or oxaliplatin. Indeed, the combination of capecitabine plus oxaliplatin (XELOX regimen) now represents a new standard of care for the metastatic disease and is also under evaluation in the adjuvant setting. The combination of new biological drugs, such as bevacizumab, with the XELOX regimen was shown to further prolong the time to progression of metastatic disease, and might reduce the risk of recurrence for those with resected colon cancer with poor risk factors. Cost-effectiveness analyses have demonstrated that, despite higher acquisition costs, capecitabine appears to be more cost effective than standard treatments for the management of colorectal cancer patients.

Hepatic Arterial Infusion of Oxaliplatin and Intravenous LV5FU2 in Unresectable Liver Metastases from Colorectal Cancer after Systemic Chemotherapy Failure

We have previously shown promising activity of hepatic arterial infusion (HAI) oxaliplatin combined with intravenous (IV) 5-fluorouracil (5-FU) and leucovorin (LV) as first-line chemotherapy in patients with colorectal liver metastases (CRLM) (intent-to-treat [ITT] objective response rate [ORR], 64%; secondary resection rate, 18%; overall survival [OS], 27 months). Whether this regimen could be beneficial after systemic chemotherapy failure is unknown. Patients with unresectable CRLM and history of systemic chemotherapy failure were treated bimonthly with HAI oxaliplatin (100 mg/m(2) 2 hours) combined with IV LV and IV bolus and infusional 5FU (modified LV5FU2 regimen). Forty-four consecutive patients (median age 56 years; median number of prior systemic chemotherapy regimens, 2 range 1-5) were included, of whom 43 (98%) had previously received oxaliplatin (n = 34), irinotecan (n = 37), or both (n = 28). Patients received a median of nine cycles of HAI oxaliplatin and IV modified LV5FU2 (range 0-25). Toxicity included grade 3-4 neutropenia (43%), grade 2-3 neuropathy (43%), and grade 3-4 abdominal pain (14%). We observed 24 partial ORs (62%) among the 39 assessable patients (ITT ORR, 55%; 95% CI, 40-69%), including 17, 12, and 12 patients who had failed to respond to prior systemic chemotherapy with FOLFIRI, FOLFOX, or both, respectively. Tumor response allowed further R0 surgical resection (n = 7) or radiofrequency ablation (n = 1) of initially unresectable CRLM in eight patients (18%). Median progression-free survival and OS were 7 and 16 months, respectively. HAI oxaliplatin and IV LV5FU2 is feasible, safe, and shows promising activity after systemic chemotherapy failure, allowing surgical resection of initially unresectable CRLM in 18% of patients.