5FU Continuous Infusion Research Articles

Real-world comparison of low- versus high-dose continuous 5FU infusion in patients receiving triplet chemotherapy plus bevacizumab for newly diagnosed metastatic colorectal cancer (mCRC).

62 Background: Several randomized trials demonstrated an overall survival (OS) benefit to triplet chemotherapy (5-FU, oxaliplatin, and irinotecan) plus bevacizumab compared to doublet chemotherapy plus bevacizumab in patients with newly diagnosed mCRC, though with higher rates of neutropenic fever and diarrhea. These trials used high-dose continuous infusion 5-FU (3,200 mg/m2/48 hours), but national guidelines suggest low-dose continuous infusion 5-FU (2,400mg/m2/48 hours) due to lower tolerance in U.S. patients. We performed a retrospective cohort study in a U.S. population to compare the effectiveness of low- vs high-dose continuous infusion 5FU in patients undergoing triplet chemotherapy plus bevacizumab for newly diagnosed mCRC. Methods: We used the nationwide Flatiron Health electronic health record-derived database, comprising de-identified patient-level structured and unstructured data curated via technology-enabled abstraction from ~280 cancer clinics. Patients with newly diagnosed mCRC who initiated triplet chemotherapy plus bevacizumab between 10/23/14 and 10/31/22 with non-missing height, weight, and dosing data were included. 5FU infusion doses of 2,000 – 2,799 mg/m2 were categorized as low-dose while those >/= 2,800 mg/m2 were categorized as high-dose. OS from first-line treatment initiation was assessed by dosing group using the Kaplan Meier method with log-rank testing. Multivariable analysis with adjustment for pre-specified variables with imbalance (defined by standardized difference < - 0.10 or > 0.10) was performed using multivariable Cox proportional hazards modeling. Missing data were imputed using multiple imputation with chained equations. Results: Among 320 patients included, 244 received low-dose and 76 patients received high-dose continuous infusion 5FU. Imbalance between low- and high-dose groups was observed in the use of 5FU bolus (23% vs 3%), year of metastatic diagnosis 2018 - 2022 (80% vs 55%), mean irinotecan dose (156.4 vs 160.5 mg/m2), left-sided primary (73% vs 64%), MMR deficiency (3% vs 6%) and mean CEA (478 vs 691 µg/L). In univariate analysis, median OS was 33 months (95% CI 26 – 39) in the low-dose group compared to 34 months (95% CI 24 – 48) in the high-dose group (HR 1.16; 95% CI 0.79 – 1.69; p = 0.44). After adjusting for imbalanced covariates, there was no difference in hazard of death between low- and high-dose groups (HR 0.99; 95% CI 0.64 – 1.53; p = 0.97). Conclusions: In this real-world, U.S. population with newly diagnosed mCRC receiving triplet chemotherapy plus bevacizumab, there was no association with survival between low- vs high-dose continuous infusion 5FU. This supports current guidelines recommending low-dose continuous infusion 5FU (2,400mg/m2/48 hours) for patients with mCRC receiving triplet chemotherapy in the U.S.

P74-5 Evaluating 5FU plasma level in colorectal cancer chemotherapy patients through continuous 5FU infusion

5-fluorouracil (5-FU) dosing has traditionally been based on body surface area (BSA) in colorectal cancer treatment. With regimens having undergone multiple refinements, including the addition of molecular targeted agents, positive prognosis has been reported for colorectal cancer.

“Decision for adjuvant treatment in stage II colon cancer based on circulating tumor DNA:The CIRCULATE-PRODIGE 70 trial”

BackgroundAdjuvant treatment for stage II colon cancer remains debated. Finding a tool to select patients at risk for disease recurrence may help the clinical decision. Circulating tumor DNA (ctDNA) has been reported recently as a potential predictive marker for disease recurrence. We thus aim to test its ability to better select stage II colon cancer patients for adjuvant therapy. MethodsThis national, phase III trial (NCT 2019-000935-15) conducted in more than 100 centers in France, plans to screen around 2640 patients in order to randomize (2:1; minimization method) 198 ctDNA positive patients. Patients aged 18 to 75 years with ECOG performance status ≤1 with R0 surgical resection of a pT3-T4aN0 colon or high rectum adenocarcinoma will be randomized within 63 days after curative-intent surgery, to adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and 5-FU bolus 400 mg/m2 then 5FU Continuous infusion 2.4 g/m²) every two weeks for 12 cycles or observation. Patients will be followed for maximum 7 years. A gain of 17.5% in 3-yr disease free survival (DFS) is expected (42.5% in the experimental arm vs. 25% in the control arm; HR:0.62; α, 5% [two-sided log-rank test]; 1-β, 80%). Secondary endpoints include 2-yr DFS, overall survival, and toxicity.Recruitement began End of January 2020.

Early experiences with triple immunochemotherapy in young adults with high-risk fibrolamellar carcinoma.

510 Background: Fibrolamellar Carcinoma (FLC) is a rare liver cancer affecting young adults without underlying liver disease. Surgery is the only proven therapy, and recurrence is common. There are no proven systemic treatments, especially for high-risk FLC (unresectable, relapse, progression, metastatic). Research suggests that immunotherapy may work. We share our experience using systemic “triple immunochemotherapy” (TT): 2 week cycles of 7 days continuous infusion 5FU or oral capecitabine, interferon alpha-2b on days 1,3,5,7 or PEG-Interferon and nivolumab on day 1. Methods: Data from all patients who received TT from 5/2018 to 9/2019 was reviewed to assess tolerability, survival and toxicity. Results: 14 patients were treated with TT of which 10 (8F,2M with a median age of 20) were evaluable. They received a median of 13 cycles (6-31). At time of analysis, the median progression free survival was 6 months, 22% longer than prior to TT, with 80% of patients (8) stable or improving, 1 progression, and 1 who died 2 months after initiating TT. For the 4 patients who achieved surgical remission, none have relapsed (PFS 9 months). Overall objective response (CR+PR) and tumor control rate (CR+PR+SD) were 60% and 80%, respectively. There were no withdrawals from treatment due to side effects, though 2 had dose adjustments. All experienced mild adverse effects, most commonly fever and headache, but only 2 patients had grade 3 toxicity. Conclusions: Our early results of TT for high-risk FLC are promising, with good tolerability and treatment response, particularly in patients who have achieved surgical CR. Further longitudinal data is needed to confirm outcomes, especially in patients still early in their treatment. [Table: see text]

Safety and efficacy of a docetaxel-5FU-oxaliplatin regimen with or without trastuzumab in neoadjuvant treatment of localized gastric or gastroesophageal junction cancer: A retrospective study.

BACKGROUNDTriplet chemotherapy, with docetaxel-5FU-oxaliplatin FLOT regimen recently became the standard perioperative treatment for localized gastric cancer (GC). An adapted regimen called TeFOX was recently tested in metastatic setting and gave promising results.AIMTo determine safety and efficacy of TeFOX perioperative regimen.METHODSThis monocentric retrospective study aims to test efficacy and safety of the perioperative TeFOX regimen given alone or in combination with trastuzumab in patients with localized GC. TeFOX consist in docetaxel (50 mg/m²) with oxaliplatin 85 mg/m² and and leucovorin (400 mg/m2) 5 FU bolus (400 mg/m2) on day 1, followed by continuous infusion of 5FU for 46 h (2400 mg/m2) every 2 wk.RESULTSThirty-three consecutive patients were included in this retrospective study. Eighteen patients have a gastroesophageal junction cancer and 11 have a GC. Median follow-up of surviving patients was 32 mo. R0 resection was obtained in 30 (91) patients. Twelve patients (36) had a pathological complete response and 8 (24) patients a nearly complete pathological response. Median OS and PFS were not reached at data base lock. We have observed 6 metastatic relapses and 1 localized relapse. No relapse was observed in patients with pathological complete responses. The most common grade 3-4 adverse events were peripheral neuropathy (21) and asthenia (20).CONCLUSIONTeFOX regimen could be safely administrated in perioperative treatment of localized GC. TeFOX and the FLOT regimen have comparable efficacy and safety profiles.

Update result of HGCSG 1403: Phase I trial of oxaliplatin/irinotecan/S-1 (OX-IRIS) as first-line chemotherapy for unresectable pancreatic cancer.

359 Background: FOLFIRINOX has become one of the standard treatment for unresectable pancreatic cancer with distant metastasis. OX-IRIS is the combination therapy of oxaliplatin (L-OHP), irinotecan (IRI) and S-1. It is the useful treatment to dispense with a continuous infusion of 5FU by administering S-1 orally. For establishing OX-IRIS therapy as a new standard treatment, we planned this study for evaluating dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Methods: This study was carried out as a multicenter phase I study. Chemotherapy-naïve patients with unresectable pancreatic cancer were included. L-OHP and IRI were administered on day 1 and 15, and S-1 was taken twice a day in day 1-14, and then 14 days were rest for 1 cycle. The primary endpoints were the frequency of DLT and estimating of MTD. Secondary endpoints were safety, response rate, progression-free survival (PFS) and overall survival (OS). Results: Between January 2016 and August 2017, 13 cases were enrolled. The patients’ backgrounds were median age 62; male /female, 9/4; the primary tumor sites head /body and tail, 8/5; ECOG PS 0/1, 7/6; UR-LA /UR-M, 4/9. Two of five enrolled in level 0 (L-OHP: 85 mg/m2, IRI: 100 mg/m2, S-1: 80 mg/m2) had DLT. One of six in level -1 (L-OHP: 65 mg/m2, IRI: 100 mg/m2, S-1: 80 mg/m2) had DLT. At level 0, 100% of cases had anemia and fatigue, 80% anorexia, diarrhea, peripheral sensory neuropathy, 60% platelet count decrease. At level -1, 100% had anemia, 75% nausea and fatigue, 63% anorexia. Response rate was 10% and disease control rate was 70% in ten cases with evaluable lesion. Median PFS was 4.1 months (95%C.I.; 0.0-8.6 months). Median OS was 13.7 months (95%C.I.; 5.9-21.5 months). Conclusions: In this study, MTD was estimated to be level 0, and determined recommended dose is level -1 for the planned future study. We are going to evaluate efficacy and safety in a phase II study. (UMIN ID: 000017002) Clinical trial information: 000017002.

196P - HGCSG1403: Phase I trial of oxaliplatin/irinotecan/S-1 (OX-IRIS) as first-line chemotherapy for unresectable pancreatic cancer

Background: In recent years, FOLFIRINOX has become one of the primary standard treatment for unresectable pancreatic cancer (PC) with distant metastasis. OX-IRIS is the combination therapy of oxaliplatin (L-OHP), irinotecan (IRI) and S-1. It is the useful treatment to dispense with a continuous infusion of 5FU by administering S-1 orally. For establishing OX-IRIS therapy as a new standard treatment, we planned this study. Methods: Chemotherapy-naïve patients with unresectable PC were included. L-OHP and IRI were administered on day 1 and 15, and S-1 was taken twice a day in day 1-14, and 14 days were rest for 1 cycle. This study used a standard 3 plus 3 design, and we evaluated safety and tolerability in 3 to 6 cases of each levels. It was assumed until 1 cycle completion for the evaluation period of dose limiting toxicity (DLT). Maximum tolerated dose (MTD) was defined as the highest dose beyond a more of one-third within DLT evaluation period. The primary endpoint was the frequency of DLT and MTD. Secondary endpoints were the frequency of adverse events, response rate, progression-free survival (PFS) and overall survival (OS). Results: Between January 2016 and August 2017, 13 cases were enrolled. The patients’ backgrounds were median age 62 years old, man/woman; 9/4, the primary tumor sites head/body and tail; 8/5, ECOG PS 0/1; 7/6, UR-LA/UR-M; 4/9. Two of five patients enrolled in level 0 (L-OHP: 85 mg/m2, IRI: 100 mg/m2, S-1: 80 mg/m2) had DLT. In two of eight patients enrolled in level -1 (L-OHP: 65 mg/m2, IRI: 100 mg/m2, S-1: 80 mg/m2), DLT was impossible to evaluate because the treatment of 1 cycle was not accomplished. And one of remaining six cases had DLT. At level 0, 100% of cases had anemia and fatigue, 80% had anorexia, diarrhea, peripheral sensory neuropathy, 60% had platelet count decrease. At level -1, 100% of cases had anemia, 75% had nausea and fatigue, 63% had anorexia. Response rate was 10% and disease control rate was 70% in ten cases with the evaluable lesion. Median PFS was 4.1 months. Conclusions: In this study, MTD was estimated to be level 0, and determined that recommended dose (RD) was level -1 in the planned future study. We are going to evaluate efficacy and the safety in a phase II study. Clinical trial identification: UMIN000017002 - 2015/04/01. Legal entity responsible for the study: Non-profit Organization: Hokkaido Gastrointestinal Cancer Study Group. Funding: Non-profit Organization: Hokkaido Gastrointestinal Cancer Study Group. Disclosure: S. Yuki: Honoraria: Yakult Honsha, Taiho Pharmaceutical. Y. Komatsu: Honoraria: Taiho Pharmaceutical; Donation: Taiho Pharmaceutical, Yakult Honsha; Research fund: Taiho Pharmaceutical. All other authors have declared no conflicts of interest.

Can we downstage locally advanced pancreatic cancer to resectable? A phase I/II study of induction oxaliplatin and 5-FU chemoradiation.

Half of patients with pancreatic adenocarcinoma (PC) present with regionally advanced disease. This includes borderline resectable and locally advanced unresectable tumors as defined by current NCCN guidelines for resectability. Chemoradiation (CH-RT) is used in this setting in attempt to control local disease, and possibly downstage to resectable disease. We report a phase I/II trial of a combination of 5FU/Oxaliplatin with concurrent radiation in patients presenting with borderline resectable and locally advanced unresectable pancreatic cancer. Patients with biopsy-proven borderline resectable or locally advanced unresectable PC were eligible. Chemotherapy included continuous infusion 5FU (200 mg/m2) daily and oxaliplatin weekly for 5 weeks in dose escalation cohorts, ranging from 30 to 60 mg/m2. Concurrent radiation therapy consisted of 4,500 cGy in 25 fractions (180 cGy/fx/d) followed by a comedown to the tumor and margins for an additional 540 cGy ×3 (total dose 5,040 cGy in 28 fractions). Following completion of CH-RT, patients deemed resectable underwent surgery; those who remained unresectable for cure but did not progress (SD, stable disease) received mFOLFOX6 ×6 cycles. Survival was calculated using Kaplan-Meier analysis. End-points of the phase II portion were resectability and overall survival. Overall, 24 subjects (15 men and 9 women, mean age 64.5 years) were enrolled between June 2004 and December 2009 and received CH-RT. Seventeen patients were enrolled in the Phase I component of the study, fifteen of whom completed neoadjuvant therapy. Reasons for not completing treatment included grade 3 toxicities (1 patient) and withdrawal of consent (1 patient). The highest dose of oxaliplatin (60 mg/m2) was well tolerated and it was used as the recommended phase II dose. An additional 7 patients were treated in the phase II portion, 5 of whom completed CH-RT; the remaining 2 patients did not complete treatment because of grade 3 toxicities. Overall, 4/24 did not complete CH-RT. Grade 4 toxicities related to initial CH-RT were observed during phase I (n=2, pulmonary embolism and lymphopenia) and phase II (n=3, fatigue, leukopenia and thrombocytopenia). Following restaging after completion of CH-RT, 4 patients had progressed (PD); 9 patients had SD and received additional chemotherapy with mFOLFOX6 (one of them had a dramatic response after two cycles and underwent curative resection); the remaining 7 patients (29.2%) were noted to have a response and were explored: 2 had PD, 4 had SD, still unresectable, and 1 patient was resected for cure with negative margins. Overall 2 patients (8.3%) in the study received curative resection following neoadjuvant therapy. Median overall survival for the entire study population was 11.4 months. Overall survival for the two resected patients was 41.7 and 21.6 months. Combined modality treatment for borderline resectable and locally advanced unresectable pancreatic cancer with oxaliplatin, 5FU and radiation was reasonably well tolerated. The majority of patients remained unresectable. Survival data with this regimen were comparable to others for locally advanced pancreas cancer, suggesting the need for more novel approaches.

Phase I/II trial of cetuximab with 5-fluorouracil and mitomycin C concurrent with radiotherapy in patients with muscle invasive bladder cancer.

4527 Background: This phase I/II trial assessed the safety, feasibility and efficacy of cetuximab (Cet) in combination with 5-fluorouracil (5FU) and mitomycin C (MMC) with concurrent radiotherapy (RT) for the treatment of muscle invasive bladder cancer (MIBC). BC2001 trial has previously reported significant improvement in locoregional control in patients (pts) with MIBC who were randomised to synchronous chemo-RT compared to RT alone (James, Hussain, Hall et al NEJM 2012). Results for phase I have been reported previously. This abstract reports the combined results of phases I/II. Methods: From September 2012 to October 2016, 33 pts were recruited (7 pts to phase I from 2 UK centres and 26 patients to phase II from 5 UK centres). Pts received loading dose of Cet 400 mg/m2 followed by weekly Cet 250 mg/m2 for 7 weeks, continuous infusion 5FU 500mg/m2/day during fractions 1-5 and 16-20 of RT and MMC 12mg/m2on day 1 in combination with radical RT 64 Gy in 32 fractions. Neoadjuvant chemotherapy was mandatory in phase I but optional in phase II. Primary outcomes in phase I were feasibility and toxicity. Primary outcome in phase II was 3 month pathological complete response (CR) rate, secondary outcomes included toxicity, progression free survival (PFS) and overall survival (OS). Results: Median age of pts was 70 (range 46.9-85.6). Treatment completion rates in phase I were RT 100%, 5FU 100 %, MMC 100%, Cet 96%. Of the 28 analysable pts, phase II primary outcome data was available for 25 pts at the time of analysis with a 3 month pathological CR rate of 88%. 5 local progressions and 4 deaths were reported. 12 pts suffered at least one SAE. Grade 4 toxicities observed were dyspnoea, atrial fibrillation, interstitial pneumonitis, sepsis, thromboembolism, neutropenia and palpitations. The commonest grade 3 toxicities were skin rash, diarrhoea, low platelet count, low white blood cell count, fever and haematuria. The most common grade 1 and 2 toxicities were diarrhoea and skin rash. Data on PFS and OS will be presented. Conclusions: It was feasible and safe to add cetuximab to full dose chemo-RT with 5FU/MMC. The CR rate is encouraging and further randomised studies with this combination are warranted. Clinical trial information: ISRCTN80733590.

A prospective randomized trial comparing capecitabine-based chemoradiotherapy with 5-FU-based chemoradiotherapy in neoadjuvant setting in locally advanced carcinoma rectum.

Fluorouracil (FU)based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. Capecitabine is an oral fluoropyrimidine that generates 5FU preferentially at the tumor site by exploiting the higher activity of the enzyme thymidine phosphorylase in tumor tissue compared with healthy tissue. As an oral agent, capecitabine can be administered in the outpatient setting, potentially providing FU exposure similar to a lowdose continuous infusion of 5FU. To compare capecitabine with 5FU, with regard to efficacy and toxicity when used in neoadjuvant setting along with radiotherapy for locally advanced carcinoma rectum. Thirty patients were enrolled, 14 in 5FU and 16 in capecitabine arm. All patients were planned for 45 Gy/25#/5 weeks pelvic radiotherapy followed by a boost of 5.4 Gy/3#/3 days. 5FU was prescribed at a dose of 500 mg/m2 #1-#5 and #21-#25 of RT and capecitabine was given at 1650 mg/m2 on RT days throughout the course of radiotherapy. A magnetic resonance imaging/computerized tomography scan was done at the start of treatment and 1 month after completion of treatment, followed by surgery. Toxicity was assessed weekly during treatment and on the first followup. Response rates and toxicity profile of capecitabinebased cathode ray tube (CRT) was similar to 5FUbased CRT with nonsignificant P values. Capecitabine may be used as an alternative in patients who do not tolerate 5FU.

Efficacy and safety of perioperative chemotherapy with 5FU-cisplatine-cetuximab in gastric and gastroesophageal junction adenocarcinomas (GGOJA): A single-arm multicenter phase II trial (FFCD 0901).

154 Background: Whilst perioperative chemotherapy (CT) combined with radical surgery offers a survival benefit over surgery alone in GGOJA, 3-year survival still needs to be improved. The purpose of this phase II study was to evaluate the efficacy and safety of the perioperative use of cetuximab combined with 5-fluorouracil and cisplatin in operable GGOJA. Methods: Untreated operable patients with a WHO Performance Status (PS) ≤ 2 and age ≤ 75 years, with localised GGOJA received 6 cycles of intravenous Cetuximab (500mg/m²), Cisplatine (50mg/m²) and LV5FU2s (folinic acid 400mg/m², 5FU bolus 400mg/m², and continuous infusion of 5FU 2400mg/m²) every 2 weeks. Surgery was planned 3-4 weeks after the end of neaodjuvant CT and postoperative CT planned for 6-8 weeks after surgery. The primary objective was a combined evaluation of tumoral response, assessed by centrally reviewed computed tomography, and major toxicities leading to neoadjuvant CT being discontinued. Sample size (63 patients) was calculated using Bryant and Day design (α=5%, Power=80%), expecting a rate of objective response of 45% and a percentage of patients without major toxicities of 90%. Results: 65 patients were enrolled from 2011 to 2013 with a median age of 60.5 years. 83.1% were men, 98.5% had a WHO PS<2, 30.8% had a gastric and 69.2% a junctional tumour, 28.5% had a stage II and 71.4% of patients a stage III tumour. With regard to the primary endpoint, 64 patients were evaluated, 29.7% (n=19) had an objective morphological tumour response and 95.3% (n=61) did not stop treatment prematurely due to major toxicity. 58 patients (89.2%) completed neoadjuvant CT as planned. The median duration of CT was 2.3 months and grade 3-4-5 toxicities were observed in 61.5% of patients. 60 patients (92.3%) underwent surgical resection with 24 significant complications (41.7%) and 2 postoperative deaths (3.4%). On histological analysis, 40 patients (71.4%) were non responders. Conclusions: Adding cetuximab to the neoadjuvant chemotherapy regimen in operable GGOJA is safe but does not show enough efficacy in the present study to meet the primary endpoint. Clinical trial information: NCT01360086.

632P - Efficacy and Safety of Perioperative Chemotherapy with 5Fu-Cisplatin-Cetuximab in Gastric and Gastroesophageal Junction Adenocarcinomas (Ggoja): a Single Arm Multicentre Phase Ii Trial (Ffcd 0901)

ABSTRACT Aim: Whilst perioperative chemotherapy (CT) combined with radical surgery offers a significant survival benefit over surgery alone in GGOJA, 3-year survival still needs to be dramatically improved. The purpose of this phase II study was to evaluate the efficacy and safety of the perioperative use of cetuximab combined with 5-fluorouracil and cisplatin in operable GGOJA. Methods: Untreated operable patients with a WHO Performance Status (PS) ≤ 2 and age ≤ 75 years, with localised GGOJA received 6 cycles of intravenous Cetuximab (500mg/m2), Cisplatin (50mg/m2) and LV5FU2s (folinic acid 400mg/m2, 5FU bolus 400mg/m2, and continuous infusion of 5FU 2400mg/m2) every 2 weeks. Surgery was planned 3-4 weeks after the end of neaodjuvant CT and postoperative CT, with the same regimen, planned for 6-8 weeks after surgery. The primary objective was a combined evaluation of tumoral response, assessed by centrally reviewed computed tomography, and major toxicities leading to neoadjuvant CT being discontinued. Sample size (63 patients) was calculated using Bryant and Day design (a = 5%, Power = 80%), expecting a rate of objective response of 45% and a percentage of patients without major toxicities of 90%. Results: 65 patients were enrolled from June 2011 to March 2013 with a median age of 60.5 years. 83.1% were men, 98.5% had a WHO PS of 0 or 1, 30.8% had a gastric and 69.2% a junctional tumour, 28.5% had a stage II and 71.4% of patients a stage III tumour. With regard to the primary endpoint, 64 patients were evaluated, 29.7% (n = 19) had an objective morphological tumour response and 95.3% (n = 61) did not stop treatment prematurely due to major toxicity. 58 patients (89.2%) received all 6 cycles of neoadjuvant chemotherapy as planned. The median duration of chemotherapy was 2.3 months and grade 3-4-5 toxicities were observed in 61.5% of patients. 60 patients (92.3%) underwent surgical resection with 24 significant complications (41.7%) and 2 postoperative deaths (3.4%). On histological analysis, 40 patients (71.4%) were non responders. Conclusions: Adding cetuximab to the neoadjuvant chemotherapy regimen in operable GGOJA is safe but does not show enough efficacy in the present study to meet the primary endpoint. Disclosure: C. Mariette: - speaker consultant Nestle - speaker Takeda - Speaker Merck Serono - Speaker Sanofi; D. Pezet: Collaboration with Novartis, Sanofi, Merck, Roche, Bayer et Lilly; O. Bouche: Merck Sereno. All other authors have declared no conflicts of interest.

519O - Final Results of Australasian Gastro-Intestinal Trials Group (AGITG) Arctic Study: AN International Audit of Raltitrexed for Patients with Cardiac Toxicity Induced by Fluoropyrimidines (FP)

ABSTRACT Background Cardiac toxicity (CT) is an uncommon but potentially fatal side effect of FP. The incidence of further CT if the same chemotherapy is continued is reported to be 20%*. Management of these patients remains poorly defined and options include continuing same dose/schedule of FP, adding a nitrate and calcium antagonist, switching administration schedule of FP, or substituting with raltitrexed, the later based primarily on case reports. Methods AGITG and OCTO (Oncology Clinical Trials Office – Oxford) members identified patients who had CT from FP, and were subsequently switched to raltitrexed. CT included angina, myocardial infarct (MI) or arrhythmia. A coronary angiogram was not mandatory. Results 42 patients were included in this clinical audit. Cancer diagnoses included colorectal (39pts), oesophageal (2) and ampullary carcinoma (1). Median age - 62 years (range 36-81). 27 patients (64%) were male. Median number of cycles prior to switching to raltitrexed was 2 (range 1-11). FP regimens included FOLFOX, CAPOX, continuous infusion 5FU, ECF, capecitabine alone. 40 patients had angina, 5 MI, and 2 arrhythmia with some patients experiencing >1 event at that time. 8 patients experienced two separate CT events, and 2 had 3 events prior to switching to raltitrexed. Following CT, 9 patients received raltitrexed alone, 32 received raltitrexed in combination with other agents or radiotherapy and one received raltitrexed alone followed by combination. Median number of raltitrexed cycles was 6 (range 1-21). One patient (CT rate 2.4%, 95% CI: 0.1-12.3) experienced a potentially related cardiac event (acute arrhythmia 5 mths into therapy) after switching to raltitrexed, a CT rate significantly lower than the 20% reported when continuing FP (exact binomial test p = 0.004). Conclusion The rate of recurrent CT after switching from FP to raltitrexed was low. The strategy of switching to raltitrexed may represent an acceptable option for patients that are deriving a benefit from FP based chemotherapy but in whom cardiac toxicity is a concern. (* Jensen SA et al. Cancer Chemotherapy & Pharm. 58:487-93, 2006). Disclosure D. Ransom: Unrestricted research grant from Astra Zeneca. All other authors have declared no conflicts of interest.

P-0024 The Efficacy and Tolerability of Modified DCF in Patients with Advanced or Recurrent Gastric Cancer: A Retrospective Analysis

ABSTRACT Introduction Although docetaxel, cisplatin and 5FU (DCF) significantly has improved TTP, and OS in gastric cancer patients, the use of DCF has restricted because of severe toxicities. In real world, the dose of DCF has frequently modified according to clinician’s experiences and intuition. In this report, we introduce new modified DCF (mDCF) regimen and report efficacy and tolerability of mDCF in advanced or recurrent gastric cancer. Methods Total 24 patients with advanced or recurrent gastric cancer treated with mDCF at Seoul Paik Hospital between Mar 2007 and June 2010 were reviewed. Treatment protocol was 60mg/m2 of docetaxel, 50mg/m2 of cisplatin on D1, and 950mg/m2/day of 5FU continuous infusion on D1-3 until disease progression or intolerance to chemotherapy. All clinical data were collected retrospectively. Results Of 24, 22 patients were assessable for response. The ORR was 37.3 % (9/24), including 1 CR, and TCR 70.8 % (17/24). Median PFS and OS were 6.13 months (95% CI, 2.5-9.7) and 8.2 months (95% CI, 3.1-13.3). Grade 3 or 4 hematologic toxicities were neutropenia in 10 patients (41.7%), anemia in 3 patients (12.5%) and thrombocytopenia 4 patients (16.7%). The treatment related death occurred in 2 patients (8.3%) due to sepsis. The median cycle of chemotherapy was 6 (range: 1-15). Half of 24 patients (50%) received chemotherapy more than 8 cycles, and 2 patients (8.3%) received 15 cycles with tolerable toxicities. In this extended chemotherapy group, median PFS and OS were 10.9 months (95% CI, 4.4-17.3) and 14.1 months (95%CI, 6.7-21.5). Conclusion The presented mDCF showed favorable ORR, TCR, and acceptable toxicity profiles in patients with advanced gastric cancer. Chemotherapy with mDCF was safely used more than 8 cycles in patients who responded to mDCF. This extended mDCF could be an alternative choice after 4 or 6 cycles mDCF.

Metronomic therapy with 5-FU, weekly nab-paclitaxel, leucovorin, and oxaliplatin, plus bevacizumab for advanced pancreatic cancer: A phase II study.

e14582 Background: The objective of this open label phase 2 study was to evaluate low-dose continuous (metronomic) chemotherapy given in conjunction with conventional anti-VEGF therapy for patients with advanced pancreatic cancer. Continuous infusion of 5FU, calcium leucovorin plus paclitaxel and oxaliplatin has been shown to be active in patients with pancreatic cancer. As a protracted low dose infusion, 5FU is anti-angiogenic and has been demonstrated to be synergistic with bevacizumab. Bevacizumab and nab-paclitaxel are synergistic as seen in the treatment of breast cancer. Methods: Since July 2008, we treated 40 patients with 5FU (180mg/m2/day x 14 days) via an ambulatory pump. Calcium leucovorin (20mg/m2) IVP, nab-paclitaxel (100mg/m2) IV as a 30 minute infusion and oxaliplatin (75mg/m2) IV as a 60 minute infusion were given on days 1, 8, and 15. Bevacizumab (5mg/kg) IV over 30 minutes was given on days 1 and 15. Cycles were repeated every 35 days. There were 24 females and 16 males. The median age was 58. 34 patients had stage IV disease. Results: The median overall survival is greater than 17 months. A partial response was observed in 50% of the patients. There were 22 patients with prior treatment, 11 of whom responded to the protocol. 34 patients began treatment with an elevation of their CA19-9 greater than 40. Of these, 26 patients were subsequently noted to have greater than 50% reduction in their CA 19-9; 17 of whom had an objective CT scan response to therapy. Toxicity (grade 3 and 4) included stomatitis, diarrhea, fatigue, nausea, neuropathy, hypertension and renal failure. Hematologic toxicity included anemia, neutropenia and thrombocytopenia. 19 patients stopped treatment due to disease progression, 18 patients stopped due totoxicity. There were no chemotherapy related deaths. Conclusions: This non-gemcitabine based regimen resulted in response rates and survival benefits greater than that which is ususally observed with gemcitabine based therapy. Low dose continuous (metronomic therapy) cytotoxic chemotherapy when combined with anti-angiogenic therapy is safe and effective for patients with advanced pancreatic cancer.

Results of Australasian Gastrointestinal Trials Group (AGITG) Arctic study: An international audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines (FP).

e13007 Background: Cardiac toxicity (CT) is an uncommon but potentially fatal side effect of FP. The incidence of further CT if the same chemotherapy is continued is reported to be 20% (Jensen SA et al. Risk factors and prevention of cardiac toxicity induced by 5-fluorouracil or capecitabine. Cancer Chemotherapy & Pharm. 58:487-93, 2006). Management of these patients remains poorly defined. Treatment options include continuing same dose and schedule of FP, adding a nitrate and calcium antagonist; switching to bolus FP; or substituting with raltitrexed. Previous publications of patients experiencing CT and switching FP to raltitrexed are limited to case reports. Methods: AGITG & OCTO (Oncology Clinical Trials Office – Oxford) members identified patients who had CT from FP, and were subsequently switched to raltitrexed. CT included angina, myocardial infarct (MI) or arrhythmia. A coronary angiogram was not mandatory. Results: 38 patients were included in clinical audit. Cancer diagnoses included colorectal (35pts), cervix (1), oesophageal (1) and ampullary carcinoma (1). Median age - 61 years (range 36-81). 24 patients (63%) were male. Median number of cycles prior to switching to raltitrexed was 2 (range 1-11). FP regimens included FOLFOX, CAPOX, continuous infusion 5FU, capecitabine alone. 35 patients had angina, 6 MI, and 1 arrhythmia with some patients experiencing >1 event at that time. 7 patients experienced two separate CT events, and 2 had three events prior to switching to raltitrexed. Following CT 8 patients received raltitrexed alone, 29 received raltitrexed in combination with other agents or radiotherapy and one received raltitrexed alone followed by combination. Median number of raltitrexed cycles was 5 (range 1-21). After switching to raltitrexed 2 patients experienced another cardiac event (5.3%, 95% CI:1.5-17.3), significantly different from 20% (p=0.023), the reported rate of cardiac toxicity due to continuing FP. Conclusions: For patients who experience CT from FP switching to raltitrexed is an option with the rate of additional cardiac events lower than previously reported for continuing same FP.

A phase I study of NK012 in combination with 5-fluorouracil with or without leucovorin in patients (pts) with advanced solid tumors.

e13076 Background: NK012 is a micelle-forming macromolecular prodrug of EHC (7-ethyl-10-hydroxycamptothecin), also known as SN-38, the active metabolite of irinotecan. Irinotecan-based regimens (including FOLFIRI) are commonly used in the treatment of gastrointestinal malignancies. The development of an improved irinotecan-based regimen either by improved efficacy, schedule, or toxicity profile, has the potential for a major role in the treatment of GI malignancies. Methods: Dose escalation study to determine the maximum tolerated dose and recommended phase II dose (RD) of NK012 (day 1) in combination with bolus 5FU/LV (400 /400 mg/m2) followed by continuous infusion 5FU (2400mg/m2 over 46 hrs) on days 1 and 15 every 28 days. Results: Twenty-three pts have been enrolled. NK012 was dosed at 16, 20, and 24 mg/m2 in combination with 5FU/LV bolus + CI 5FU. Two of 3 pts at 24 mg/m2 required a delay in the day 15 treatment due to myelosuppression. As a result, 20 mg/m2 was determined to be the recommended NK012 dose in combination with 5FU/LV bolus + CI 5FU. The protocol was amended to eliminate the bolus 5FU/LV due to the potential for added myelosuppression, and NK012 was re-escalated with CI 5FU only. NK012 was dosed at 24 and 28 mg/m2. One DLT (nausea/vomiting requiring hospitalization) was reported among 6 pts treated at 28 mg/m2. The RD of NK012 in combination with CI 5FU is 28 mg/m2. Treatment-related toxicities included nausea (61%, 13% gr 3), fatigue (48%), neutropenia (44% gr 3-4), vomiting (35%, 4% gr 3), diarrhea (30%), anorexia (30%), stomatitis (26%), and alopecia (26%). Six pts (including 3 pancreatic) remained on study for > 4 cycles, and two continued treatment for ≥ 1 year (colon, pancreatic). Conclusions: The combination of NK012 and CI 5FU is well tolerated, with NK012 administered at the recommended single-agent dose of 28 mg/m2. Further exploration of the regimen is warranted, particularly in patients with GI malignancies.

Phase II trial evaluating a 12-week regimen of interdigitating FOLFOX chemotherapy plus pelvic chemoradiation for the simultaneous treatment of primary and metastatic rectal cancer.

3629 Background: Current chemotherapy regimens used during chemoradiation (CRT) are adequate for radiosensitization but suboptimal for systemic control. The aim of this study was to assess tolerability, and local/systemic benefits of new regimen delivering intensive chemotherapy and radical radiotherapy in an interdigitating manner. Methods: Phase II prospective study for patients (pts) with untreated simultaneous symptomatic primary and metastatic rectal cancer. The treatment regimen: 12 weeks long. FOLFOX chemotherapy (oxaliplatin 100mg/m2, leucovorin 200mg/m2, 5-FU 400mg/m2 bolus, all day 1, and 5FU continuous infusion [CI] 2.4 g/m2/46 hours) was given in weeks 1, 6, and 11. Pelvic CRT: 25.2 Gy in 3 weeks, 1.8 Gy/fr, with concurrent oxaliplatin 85mg/m2 day 1 and 5-FU CI 200mg/m2/day given in weeks 3-5, and 8-10. Pts received, in 12 weeks, 3 courses of FOLFOX and pelvic radiation 50.4 Gy with concurrent oxaliplatin/5-FU. All pt were staged with CT, MRI and FDG-PET before and post-treatment. Results: 26 pts treated. The mean age was 61 years, 69% male. Rectal primary MRI stage was T2 4%, T3 81% and T4 15%. Liver and lung metastases were present in 81%, and 35% of pts, respectively: 38% of patients had more than one site of metastatic disease. 24 pts (92%) completed the 12-week treatment regimen. All pts received the planned radiation dose. 65% of pts received the planned number of oxaliplatin courses with 88% of pts receiving at least 75% of the protocol oxaliplatin dose. In this 12-week period, grade 3 toxicities were neutropenia 23%, diarrhoea 15%, and radiation perineal skin reaction 12%. Only grade 4 toxicity was neutropenia: 15%. PET metabolic response (CR+PR) rate for rectal primary was 96%. Overall PET metabolic response rate for metastatic disease was 60% (CR rate 16%). Conclusions: It is thus feasible to deliver intensive chemotherapy and radical radiotherapy in an interdigitating manner to treat both primary and metastatic rectal cancer simultaneously. High completion and response rates are encouraging. This regimen is the subject of a current phase II neoadjuvant trial for resectable rectal cancer (TROG 09.01).

Relationship between treatment duration and outcomes in patients receiving concurrent chemoradiotherapy (CCRT) and surgery for locoregionally advanced (LRA) esophageal and gastroesophageal junction (E/GEJ) adenocarcinoma (ACA).

e14665 Background: Retrospective studies in breast, colon, and head and neck cancer have suggested that delays in administration of adjuvant chemotherapy result in inferior outcomes. We explore this question in patients with LRA E/GEJ ACA. Methods: From 11/99 to 7/06, 152 patients with cT3, N1, or M1a disease were enrolled on one of two clinical trials at the Cleveland Clinic. Two courses of CCRT consisting of 30Gy radiation (@1.5Gy BID) with continuous infusion cisplatin (20mg/m2/day x 4 days) and 5Fu (1000mg/m2/d x 4 days) were given both before and after surgical resection. In the second trial, 75 patients also received gefitinib during the 4 week induction and for a total of two years postoperatively. Using recursive partitioning analysis (RPA), we retrospectively explored the relationship between treatment duration and loco-regional control (LRC), distant metastatic control (DMC), freedom from recurrence (FFR), and overall survival (OS) in the 115 patients (76%) who completed all treatment. Outcomes were estimated using the Kaplan-Meier method and compared among groups using the log-rank test. Results: RPA analysis identified three groups of patients: 19 patients in whom resection occurred ≤45 days from the start of CCRT to resection (short treatment), 63 patients who underwent resection >45 days from the start of CCRT and required <50 days to complete treatment after surgery (intermediate treatment), and 33 patients who underwent resection >45 days from the start of CCRT but required ≥50 days to complete treatment after surgery (prolonged treatment). With a median follow-up of 90 (range 57-126) months, we found that patients with shorter treatment times had better 5 year DMC [64% (short) v 26% (intermediate) v 16% (prolonged); p=0.004], FFR [57% (short) v 23% (intermediate) v 16% (prolonged); p=0.015)], and OS [42% (short) v 30% (intermediate) v 12% (prolonged); p=0.08]. LRC was not different between the groups. Conclusions: Treatment delays in patients receiving multimodality therapy for LRA E/GEJ ACA may result in a greater risk of recurrence and decreased survival.

Safety and feasibility of outpatient TPX regimen.

e16057 Background: TPF has emerged as standard induction regimen in head and neck cancers. Along with docetaxel and platinum it involves continuous infusion of 5FU, which requires a prolonged admission or use of infusional devices, with added cost of treatment, not practical in many clinical situations and situations with limited resources. Keeping this in view, to make the schedule cost effective and outpatient based, we attempted to replace 5FU with oral capecitabine and study the safety and feasibility of TPX regimen (docetaxel, carboplatin and capecitabine) in advanced cancer patients. Methods: 12 patients (8 male, 4 female, age 51-67, median 58) with advanced metastatic disease, where palliative TPF regimen is generally used ,were prospectively planned to receive fixed dose combination of TPX regimen- docetaxel 120 mg day 1, carboplatin 450 mg day 2 and tab capecitabine 2000mg per day, in two divided doses, for five days q 3 weeks. There were 2 cases of cervical cancer, 3- GI tract and rest 7 had head and neck cancer. They were analysed for toxicity and tolerability. Results: In all 12 patients were given 39 courses of TPX regimen. The toxicities included weakness in 2/39 courses, loss of appetite 2/39, neutropenia grade 1 in 3/39, grade 2 in 3/39. During two course grade 3 neutropenia requiring intervention was recorded. The mucositis grade 1-2 was seen only on two occasions in previously radiated patients. There was no incidence of diarrhea. The treatment was well tolerated. All courses were given on time, and there were no treatment delays related to toxicity. Conclusions: TPX appears to be safe and feasible outpatient alternative to TPF. It has no infusional component allowing it to be used in day care setting. Efficacy data in bigger cohort is warranted.