Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial

BackgroundTo compare capecitabine/cisplatin with 5-fluorouracil/cisplatin as first-line treatment for advanced gastric cancer (AGC).Patients and methodsIn this randomised, open-label, phase III study, patients received cisplatin (80 mg/m² i.v. day 1) plus oral capecitabine (1000 mg/m² b.i.d., days 1–14) (XP) or 5-FU (800 mg/m²/day by continuous infusion, days 1–5) (FP) every 3 weeks. The primary end point was to confirm noninferiority of XP versus FP for progression-free survival (PFS).ResultsA total of 316 patients were randomised to XP (n = 160) or FP (n = 156). In the per-protocol population, median PFS for XP (n = 139) versus FP (n = 137) was 5.6 versus 5.0 months. The primary end point was met with an unadjusted hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.63–1.04, P < 0.001 versus noninferiority margin of 1.25]. Median overall survival was 10.5 versus 9.3 months for XP versus FP (unadjusted HR = 0.85, 95% CI 0.64–1.13, P = 0.008 versus noninferiority margin of 1.25). The most common treatment-related grade 3/4 adverse events in XP versus FP patients were as follows: neutropenia (16% versus 19%), vomiting (7% versus 8%), and stomatitis (2% versus 6%).ConclusionsXP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC. XP can be considered an effective alternative to FP.     

Cetuximab with irinotecan,folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study

BackgroundCetuximab plus irinotecan/folinic acid/5-fluorouracil (5-FU) (IF) was evaluated as first-line treatment of patients with advanced gastric cancer and gastroesophageal junction tumors. Preplanned analyses of the influence of tumor biomarkers on treatment outcome were carried out.Patients and methodsPatients received weekly cetuximab (400 mg/m² on day 1, subsequently 250 mg/m²) plus irinotecan (80 mg/m²) and a 24-hour continuous infusion of folinic acid (200 mg/m²) and 5-FU (1500 mg/m²) on days 1, 8, 15, 22, 29 and 36 of a 50-day cycle, until progressive disease (PD).ResultsThe most common grade 3/4 toxic effects in 49 patients were diarrhea (15%) and skin toxic effects (14%). In 48 assessable patients, the overall response rate was 46% and disease control rate was 79%. Median progression-free survival (PFS) and overall survival (OS) was 9.0 months [95% confidence interval (CI) 7.1–15.6] and 16.5 months (95% CI 11.7–30.1), respectively. Tumor response was more common than nonresponse in epidermal growth factor receptor-expressing tumors (P = 0.041). Tumor PTEN expression was associated with longer PFS (P = 0.035) and OS (P = 0.0127) than no PTEN expression.ConclusionCetuximab plus IF was well tolerated and efficacy data were encouraging. This treatment combination and the role of selected biomarkers are under investigation in the ongoing phase III EXPAND trial.     

Cetuximab plus cisplatin–5-fluorouracil versus cisplatin–5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie

BackgroundThis study assessed the activity of the mAb cetuximab in combination with cisplatin and 5-fluorouracil (5-FU) in advanced esophageal squamous cell carcinoma.Patients and methodsFor a maximum of six 29-day cycles, patients received cisplatin 100 mg/m², day 1, plus 5-FU 1000 mg/m², days 1–5 (CF), either alone or in combination with cetuximab (CET–CF; 400 mg/m² initial dose followed by 250 mg/m² weekly thereafter). The primary end point was tumor response. Tumor material was obtained for analysis of KRAS mutation status.ResultsSixty-two eligible patients were included, 32 receiving CET–CF and 30 CF. Cetuximab did not exacerbate grade 3/4 toxicity, except for rash (6% versus 0%) and diarrhea (16% versus 0%). The overall response rate according to RECIST criteria was 19% and 13% and the disease control rate 75% and 57% for the CET–CF and CF arms, respectively. With a median follow-up of 21.5 months, the median progression-free survival was 5.9 and 3.6 months and median overall survival 9.5 and 5.5 months for CET–CF and CF, respectively. No KRAS codon 12/13 tumor mutations were identified in 37 evaluated samples.ConclusionCetuximab can be safely combined with CF chemotherapy and may increase the efficacy of standard CF chemotherapy.     

Phase II Study of Irinotecan plus Leucovorin and Bolus 5-Fluorouracil as First- or Second-Line Chemotherapy in Patients with Advanced Gastric or Esophageal-Gastric Junction Adenocarcinoma

Abstract

The aim of this study was to evaluate the activity and safety of 5-fluorouracil (5-FU) / leucovorin (LV) and irinotecan as first- or second-line treatment in patients with advanced gastric adenocarcinoma. Treatment consisted of irinotecan 80 mg/m² intravenously (i.v.), followed by LV 200 mg/m² (i.v.) and 5-FU 450 mg/m² as an i.v. bolus, administered weekly for 6 weeks, followed by a 2-week rest period. Thirty-one patients (23 chemo-naïve, 8 chemo-exposed) were enrolled. The overall response rate was 22.6% and the disease control rate was 38.7%. Among the patients who received the regimen as first-line treatment, objective response rate was 30.4% and the disease control rate was 52.1%. However, progression of the disease was recorded in all the patients receiving the combination as second-line chemotherapy. The median time to disease progression (TTP) was 4 months and the median duration of survival was 7 months. The median TTP was 6 months for patients treated with first-line chemotherapy and 2.5 for those who received study treatment as second line. Furthermore, the median survival duration was 8 months and 6 months, respectively. The most frequent grade 3 toxicity was febrile neutropenia. Grade 3 non-hematological toxicities were rare. There were no treatmentrelated deaths.

The combination of 5-FU/LV and irinotecan as first-line treatment was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation would be worthwhile, particularly in elderly or debilitated patients who cannot tolerate aggressive chemotherapy.     

A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease

BackgroundThis study compared irinotecan plus cisplatin (IP) with etoposide plus cisplatin (EP) in small-cell lung cancer patients with extensive disease.Patients and methodsPatients were randomly assigned to receive cisplatin 80 mg/m² and either irinotecan 65 mg/m², days 1 and 8 or etoposide 100 mg/m², days 1–3, every 3 weeks.ResultsBaseline characteristics were balanced between patients receiving IP (N = 202) or EP (N = 203). Median overall survival was nonsignificantly superior for patients receiving IP versus EP, 10.2 versus 9.7 months [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.65–1.01, P = 0.06] and 1- and 2-year survival rates were 41.9% versus 38.9% and 16.3% versus 8.2%, respectively. Noninferiority of IP versus EP was established, upper bound of the 95% CI of HR 1.01 (prespecified margin IP/EP <1.25). Overall response (39.1% versus 46.6%) and time to tumor progression (5.4 versus 6.2 months) were not superior for IP. Grade 3/4 vomiting (10.9% versus 4.4%) and diarrhea (15.4% versus 0.5%) were more common in the IP versus EP arm; grade 3/4 neutropenia was more frequent in the EP (59.6%) versus IP arm (38.1%).ConclusionsOur data demonstrate the noninferiority of IP versus EP for survival in primarily Western patients with SCLC-ED. A meta-analysis is required to finally assess the role of irinotecan in this setting.     

A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer

BackgroundStudies indicate that adjuvant 5-fluorouracil (5-FU) with folinic acid (FA) in colorectal cancer patients with completely resectable liver-limited metastases (LMCRC) offers clinical benefit over surgery alone. This phase III trial compared FOLFIRI with simplified 5-FU/FA in this setting.Patients and methodsLMCRC patients were randomized to receive every 14 days, FA, 400 mg/m² infused over 2 h, followed by 5-FU as a 400 mg/m² i.v. bolus, followed by continuous 5-FU infusion, 2400 mg/m² over 46 h (LV5FUs) with or without irinotecan: 180 mg/m² infusion (FOLFIRI). The primary end point was disease-free survival (DFS); secondary end points included overall survival (OS) and safety.ResultsTreated patients (n = 306) were balanced for critical prognostic factors in each arm. Median DFS in patients receiving LV5FUs was 21.6 versus 24.7 months for FOLFIRI [hazard ratio (HR) 0.89, log-rank P = 0.44]. No significant differences were found in OS. A trend was observed for improved DFS in patients receiving FOLFIRI within 42 days of surgery (HR 0.75, P = 0.17). Grade 3/4 toxic effects were more common in patients treated with FOLFIRI versus LV5FUs (47% versus 30%) with neutropenia being most common (23% versus 7%).ConclusionFOLFIRI in the adjuvant treatment of LMCRC showed no significant improvement in DFS compared with LV5FUs.     

Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan,oxaliplatin and 5-fluorouracil

BackgroundStandard weekly cetuximab and irinotecan (CetIri) is an effective regimen in heavily pretreated patients with advanced colorectal cancer (ACRC). Inspired by a pharmacokinetic study demonstrating no differences between weekly and biweekly cetuximab, we present the results of 74 consecutive patients treated with biweekly CetIri.MethodsBiweekly CetIri schedule: cetuximab 500 mg/m², first course was given as a 120-min infusion followed 1 h later by irinotecan 180 mg/m² as a 30-min infusion. Subsequent courses of cetuximab were given in 60 min, immediately followed by irinotecan—resulting in an overall treatment time of 90 min.ResultsAll patients had ACRC resistant to 5-fluorouracil and irinotecan and 95% to oxaliplatin. Median age was 63 years, median performance status was 0. Median duration of therapy was 4.3 months. Response rate was 25%. Median progression-free survival and overall survival were 5.4 months and 8.9 months, respectively, comparable to own historical controls receiving weekly CetIri. Grade 3–4 toxicity was rare (skin 7%, nail 3%, diarrhoea 10%, fatigue 3%, neutropenia 9%). One patient experienced severe allergic reaction.ConclusionSalvage therapy with simplified biweekly CetIri is a convenient, effective and well-tolerated regimen in heavily pretreated patients with ACRC. A confirmatory phase II study is ongoing.     

Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: Final results from a randomised phase ii study of bevacizumab plus 5-fluorouracil,leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study)

BackgroundThe combination of bevacizumab and bolus 5-fluorouracil, leucovorin and irinotecan is highly effective in patients with metastatic colorectal cancer (mCRC). This randomised, multicenter, non-comparative phase II trial assessed the efficacy and safety of bevacizumab plus oral capecitabine plus irinotecan (XELIRI) or infusional 5-fluorouracil, leucovorin plus irinotecan (FOLFIRI) as first-line therapy for patients with mCRC.Patients and MethodsPatients received bevacizumab 7.5 mg/kg on day 1 plus XELIRI (irinotecan 200 mg/m² on day 1 and oral capecitabine 1000 mg/m² bid on days 1–14) every 3 weeks or bevacizumab 5 mg/kg on day 1 plus FOLFIRI (5-fluorouracil 400 mg/m² on day 1 plus 2400 mg/m² as a 46-h infusion, leucovorin 400 mg/m² on day 1, and irinotecan 180 mg/m² on day 1) every 2 weeks. Patients aged ?65 years received a lower dose of capecitabine (800 mg/m² twice daily). The primary endpoint was 6-month progression-free survival (PFS) rate.ResultsA total of 145 patients were enrolled (bevacizumab–XELIRI, n = 72; bevacizumab–FOLFIRI, n = 73). The 6-month PFS rate was 82% (95% confidence intervals (CI) 71–90%) in the bevacizumab–XELIRI arm and 85% (95% CI 75–92%) in the bevacizumab–FOLFIRI arm. In both the bevacizumab–XELIRI and bevacizumab–FOLFIRI arms, median PFS and overall survival (OS) were 9 and 23 months, respectively. The most frequent toxicities were grade 3/4 neutropenia (bevacizumab–XELIRI 18%; bevacizumab–FOLFIRI 26%) and grade 3 diarrhoea (12% and 5%, respectively).ConclusionsThis randomised non-comparative study demonstrates that bevacizumab–XELIRI and bevacizumab–FOLFIRI are effective regimens for the first-line treatment of patients with mCRC with manageable toxicity profiles.     

Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study

Background: Irinotecan plus infusional 5-fluorouracil/leucovorin(FOLFIRI) is accepted as a reference treatment for the first-linetreatment of patients with metastatic colorectal cancer (MCRC).The aim of this study was to demonstrate that a regimen withoutleucovorin (LV) (FUIRI) is not inferior to the standard FOLFIRI(response rate). Patients and methods: Chemotherapy-naive patients with MCRCwere randomized to receive either irinotecan (180 mg/m² on day1) + 5-fluorouracil (5-FU) (400 mg/m² bolus and 600 mg/m² 22-hinfusion) + LV (200 mg/m² on days 1–2) (FOLFIRI) every2 weeks or irinotecan (80 mg/m²) + 5-FU (2.250 mg/m² 48-h infusion)(FUIRI) weekly. Results: In all, 346 patients were included, 173 in each arm.In the intention-to-treat analysis, the response rates for FOLFIRIand FUIRI were 57% [95% confidence interval (CI) 49% to 64%]and 51% (95% CI 43% to 59%), respectively (P = 0.2809). No statisticallysignificant differences were observed between FOLFIRI and FUIRIregarding median progression-free survival (8.3 versus 8.4 months;P = 0.4339) nor median overall survival (21.6 versus 19.2 months;log-rank test P = 0.2941). Grade 3/4 neutropenia was significantlymore frequent on FOLFIRI arm (27% versus 9%), while the proportionof diarrhea was higher on FUIRI arm (21% versus 42%). Conclusion: FUIRI represents a valid alternative without LVto the FOLFIRI regimen as MCRC first-line treatment. Key words: colorectal cancer, 5-fluorouracil, irinotecan Received for publication May 7, 2008. Revision received July 11, 2008. Accepted for publication July 14, 2008.     

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer

BackgroundSome trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer.Patients and methodsPatients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m² day 1, LV 100 mg/m² as 2 h infusion and 5-FU 400 mg/m² as bolus, days 1 and 2 followed by 600 mg/m²/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm).ResultsFrom February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85–1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82–1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively.ConclusionsA more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy.Clinical trial registrationClinicalTrials.gov Identifier: NCT01640782.     

Cetuximab in combination with weekly 5-fluorouracil/folinic acid and oxaliplatin (FUFOX) in untreated patients with advanced colorectal cancer: a phase Ib/II study of the AIO GI Group

BackgroundThis two-part phase Ib/II study investigated the feasibility of administering cetuximab in combination with oxaliplatin and infusional 5-fluorouracil (5-FU)/folinic acid (FA) in a weekly schedule (AIO FUFOX protocol) as first-line treatment in patients with epidermal growth factor receptor-detectable advanced colorectal cancer.Patients and methodsCetuximab was administered weekly: 400 mg/m² initial dose, then 250 mg/m² and FUFOX: oxaliplatin 50 mg/m², FA 500 mg/m² and 5-FU as a 24-h infusion at either 1500 or 2000 mg/m² administered for 4 weeks followed by a 1-week rest (one cycle).ResultsDose-limiting toxicity (grade 3 diarrhea) occurred in 3 of 14 assessable patients receiving 5-FU at standard 2000 mg/m². This dose was administered to a further 25 patients. Cetuximab combined with FUFOX was generally well tolerated with the most common grade 3/4 adverse events being diarrhea (27%) and paresthesia (16%). The confirmed response rate for patients receiving 5-FU at standard 2000 mg/m² (N = 41) was 56%, with a median duration of 9.3 months. Median progression-free and overall survival times including all 49 patients were 8.1 (95% confidence interval 6.0–9.7) and 28.2 months, respectively. Cetuximab pharmacokinetics seemed not to be different for combination with FUFOX compared with cetuximab/irinotecan combinations.ConclusionThis protocol is well tolerated and shows promising efficacy supporting further investigation.     

Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial

OLIVIA, a multinational phase II study, suggests that bevacizumab plus FOLFOXIRI improves outcomes, including response rates, resection rates, and progression-free survival, compared with bevacizumab plus mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer.BackgroundFor patients with initially unresectable liver metastases from colorectal cancer, chemotherapy can downsize metastases and facilitate secondary resection. We assessed the efficacy of bevacizumab plus modified FOLFOX-6 (5-fluorouracil/folinic acid, oxaliplatin) or FOLFOXIRI (5-fluorouracil/folinic acid, oxaliplatin, irinotecan) in this setting.Patients and methodsOLIVIA was a multinational open-label phase II study conducted at 16 centres in Austria, France, Spain, and the UK. Patients with unresectable liver metastases were randomised to bevacizumab (5 mg/kg) plus mFOLFOX-6 [oxaliplatin 85 mg/m², folinic acid 400 mg/m², 5-fluorouracil 400 mg/m² (bolus) then 2400 mg/m² (46-h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m², irinotecan 165 mg/m², folinic acid 200 mg/m², 5-fluorouracil 3200 mg/m² (46-h infusion)] every 2 weeks. Unresectability was defined as ≥1 of the following criteria: no possibility of upfront R0/R1 resection of all lesions; <30% residual liver volume after resection; metastases in contact with major vessels of the remnant liver. Resectability was evaluated by multidisciplinary review. The primary end point was overall resection rate (R0/R1/R2). Efficacy end points were analysed by intention-to-treat analysis.ResultsIn patients assigned to bevacizumab–FOLFOXIRI (n = 41) or bevacizumab–mFOLFOX-6 (n = 39), the overall resection rate was 61% [95% confidence interval (CI) 45% to 76%] and 49% (95% CI 32% to 65%), respectively (difference 12%; 95% CI -11% to 36%). R0 resection rates were 49% and 23%, respectively. Overall tumour response rates were 81% (95% CI 65% to 91%) with bevacizumab–FOLFOXIRI and 62% (95% CI 45% to 77%) with bevacizumab–mFOLFOX-6. Median progression-free survival (PFS) was 18·6 (95% CI 12.9–22.3) months and 11·5 (95% CI 9.6–13.6) months, respectively. The most common grade 3–5 adverse events were neutropenia (bevacizumab–FOLFOXIRI, 50%; bevacizumab–mFOLFOX-6, 35%) and diarrhoea (30% and 14%, respectively).ConclusionsBevacizumab–FOLFOXIRI was associated with higher response and resection rates and prolonged PFS versus bevacizumab–mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer. Toxicity was increased but manageable with bevacizumab–FOLFOXIRI.ClinicalTrials.govNCT00778102.     

A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction

BackgroundThe combination of irinotecan with 5-fluorouracil demonstrates efficacy with tolerable safety in the first-line treatment of metastatic gastroesophageal cancer (mGC). This randomized phase II trial compared for the first time capecitabine with irinotecan or cisplatin in this setting.Patients and methodsPatients were randomly assigned to receive 3-week cycles of capecitabine 1000 mg/m², twice daily for 14 days, with on day 1 either irinotecan 250 mg/m² (XI) or cisplatin 80 mg/m² (XP). The primary end point was overall response rate (ORR) and secondary end points included progression-free survival (PFS), overall survival (OS) and safety.ResultsOf 118 patients recruited, 112 were eligible for safety analysis and 103 for efficacy analysis. In the XI and XP treatment arms, there were no marked differences in ORR, 37.7% versus 42.0%, and median PFS, 4.2 versus 4.8 months, although median OS was longer, 10.2 versus 7.9 months, respectively. Grade 3/4 toxicity was higher in the XP regimen for thrombocytes (18.2% versus 1.8%), nausea (23.6% versus12.3%) and vomiting (16.4% versus 1.8%) and in the XI arm for diarrhea (22.8% versus 7.3%).ConclusionThe comparable activity and safety of the XI and XP regimens establish XI as a relevant platinum-free first-line treatment choice for patients with mGC.     

Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer

Purpose

To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with metastatic colorectal cancer (mCRC).

Patients and methods

A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m², 5-fluorouracil 2000 mg/m², folinic acid 500 mg/m² weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m² applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS).

Results

A total of 479 eligible patients were randomly assigned. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm [hazard ratio = 1.14; 95% confidence interval (CI) 0.94-1.37; P = 0.178]. Comparable results were also obtained for overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio = 1.08, P = 0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P = 0.001). Most frequent grades 1-4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3-4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P = 0.006)

Conclusion

mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first-line treatment of metastatic colorectal cancer.     

Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015.

BACKGROUND: The study aimed to demonstrate the noninferiority of capecitabine to 5-fluorouracil (5-FU)/folinic acid (FA), in relation to progression-free survival (PFS) after first-line treatment of metastatic colorectal cancer and the benefit of adding celecoxib (C) to irinotecan/fluoropyrimidine regimens compared with placebo (P). PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI: irinotecan (180 mg/m(2) i.v. on days 1, 15 and 22); FA (200 mg/m(2) i.v. on days 1, 2, 15, 16, 29 and 30); 5-FU (400 mg/m(2) i.v. bolus, then 22-h, 600 mg/m(2) infusion) or CAPIRI: irinotecan (250 mg/m(2) i.v. infusion on days 1 and 22); capecitabine p.o. (1000 mg/m(2) b.i.d. on days 1-15 and 22-36). Patients were additionally randomly assigned to receive either placebo or celecoxib (800 mg: 2 x 200 mg b.i.d.). RESULTS: The trial was closed following eight deaths unrelated to disease progression in the 85 enrolled (629 planned) patients. Response rates were 22% for CAPIRI + C, 48% for CAPIRI + P, 32% for FOLFIRI + C and 46% for FOLFIRI + P. Median PFS and overall survival (OS) times were shorter for CAPIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months) and celecoxib versus placebo (PFS 6.9 versus 7.8 months and OS 18.3 versus 19.9 months). CONCLUSION: Due to the small sample size following early termination, no definitive conclusions can be drawn in relation to the noninferiority of CAPIRI compared with FOLFIRI.     

S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized,open-label,phase III,noninferiority trial

BackgroundCombination therapy with oral fluoropyrimidine and irinotecan has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). We carried out a randomized, open-label, phase III trial to determine whether S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab in terms of progression-free survival (PFS).Patients and methodsPatients from 53 institutions who had previously untreated mCRC were randomly assigned (1 : 1) to receive either mFOLFOX6 or CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; a 3-week regimen: intravenous infusions of irinotecan 150 mg/m² and bevacizumab 7.5 mg/kg on day 1, oral S-1 80 mg/m² twice daily for 2 weeks, followed by a 1-week rest; or a 4-week regimen: irinotecan 100 mg/m² and bevacizumab 5 mg/kg on days 1 and 15, S-1 80 mg/m² twice daily for 2 weeks, followed by a 2-week rest). The primary end point was PFS. The noninferiority margin was 1.25; noninferiority would be established if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) of the control group versus the experimental group was less than this margin.ResultBetween June 2012 and September 2014, 487 patients underwent randomization. Two hundred and forty-three patients assigned to the control group and 241 assigned to the experimental group were included in the primary analysis. Median PFS was 10.8 months (95% CI 9.6–11.6) in the control group and 14.0 months (95% CI 12.4–15.5) in the experimental group (HR 0.84, 95% CI 0.70–1.02; P < 0.0001 for noninferiority, P = 0.0815 for superiority). One hundred and fifty-seven patients (64.9%) in the control group and 140 (58.6%) in the experimental group had adverse events of grade 3 or higher.ConclusionS-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab with respect to PFS as first-line treatment of mCRC and could be a new standard treatment.Clinical trials numberUMIN000007834     

Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma

BackgroundWe aimed to investigate the efficacy and tolerability of sorafenib combined with cisplatin and 5-fluorouracil (5-FU) in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC).Patients and methodsIt was a Simon two-stage designed trial. Chemotherapy-naive patients with recurrent or metastatic disease were enrolled. The regimen was sorafenib 400 mg orally b.i.d., cisplatin 80 mg/m² i.v. day 1, and 5-FU 1000 mg/m²/day CIV for 4 days, repeated every 21 days. After a maximum of six cycles of chemotherapy, patients received maintenance of sorafenib.ResultsIn total, 54 patients were enrolled. The objective response rate reached 77.8%, including 1 complete response and 41 partial responses. The median progression-free survival was 7.2 months (95% CI 6.8–8.4 months), and the median overall survival was 11.8 months (95% CI 10.6–18.7 months). Major toxic effects included hand–foot skin reaction, myelosuppression, and gastrointestinal (GI) reaction. The incidence of hemorrhage was 22.2%, and one patient with liver metastases died of GI bleeding. Contrast-enhanced ultrasonography was carried out in a subset of patients with liver metastases.ConclusionCombination of sorafenib, cisplatin (80 mg/m²) and 5-FU (3000 mg/m²) was tolerable and feasible in recurrent or metastatic NPC. Further randomized trials to compare sorafenib plus cisplatin and 5-FU with standard dose of cisplatin plus 5-FU in NPC are warranted.     

Retrospective Comparison of Two Different Schedules of Irinotecan, 5-Fluorouracil and Folinic Acid in Previously Untreated Patients with Advanced Colorectal Carcinoma: A Single Institution Experience

Abstract

Purpose: To compare efficacy and tolerability of weekly irinotecan combined with 5-fluorouracil (5-FU) bolus and folinic acid (FA) regimen (IFL) versus biweekly irinotecan with infusional 5-FU and FA (FOLFIRI) in patients (pts) with advanced stage colorectal cancer.

Patients and Methods: Treatments outcome of 86 pts (IFL - 38 pts, FOLFIRI - 48 pts) was evaluated. Chemotherapy regimens were as follows: IFL - intravenous (i.v.) infusion irinotecan 125 mg/m² over 90 min and 5-FU 500 mg/m² preceded by FA 20 mg/m² both given by i.v. bolus injection, all repeated on days 1, 8, 15 and 22 every 6 weeks; FOLFIRI - i.v. irinotecan 180 mg/m² on days 1 and 15 with subsequent FA 200 mg/m² administered as a 2-hour infusion and i.v. bolus injection of 400 mg/m² 5-FU immediately followed by 22-hour i.v. infusion of 600 mg/m² 5-FU on days 1, 2, 15 and 16 every 4 weeks. Treatment continued until disease progression or unacceptable toxicity.

Results: A total of 152 (mean - 4) IFL cycles and 328 (mean - 6) FOLFIRI cycles were administered. Average dose intensity was 0.8 and 0.78 respectively. Toxicities were mild and manageable for both regimens evaluated. Overall response rate was 36.8% in IFL arm and 44.7 % in FOLFIRI arm. At the median follow-up of 16 months in IFL arm and 14 months in FOPFIRI arm the two year survival was 38% and 45%, the median survival was 18 months and 21.5 months, and the median progression free survival was 6 months and 9.4 months respectively.

Conclusions: In our experience, both IFL and FOLFIRI regimens have acceptable toxicity at a similar level of dose intensity. Compared to IFL, FOLFIRI seems to improve progression-free survival.     

Irinotecan combined with 5-fluorouracil and leucovorin third-line chemotherapy after failure of fluoropyrimidine, platinum, and taxane in gastric cancer: treatment outcomes and a prognostic model to predict survival

Background

The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival.

Methods

Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m² in a 2-h infusion) on day 1, and then leucovorin (200 mg/m² in a 2-h infusion) and 5-FU (a 400 mg/m² bolus, followed by 600 mg/m² in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m² in a 2-h infusion) on day 1, and then leucovorin (400 mg/m² in a 2-h infusion) and 5-FU (a 400 mg/m² bolus, followed by 2400 mg/m² in a 46-h continuous infusion) on day 1.

Results

A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7–2.5] and 5.6 months (95 % CI, 4.7–6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS.

Conclusions

The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.     

A phase II study of paclitaxel combined with infusional 5-fluorouracil and low-dose leucovorin for advanced gastric cancer

Purpose The aim of this study was to investigate the efficacy and safety of the combination chemotherapy of paclitaxel, infusional 5-fluorouracil (5-FU) and leucovorin (FLT regimen) in advanced gastric cancer. The primary end point was the time to progression (TTP). Methods Patients with evaluable disease with or without measurable lesions received 175 mg/m² paclitaxel on day 1 followed by 20 mg/m² leucovorin and 24-h infusion of 5-FU 1,000 mg/m² (day 1-3) repeated every 3 weeks. Results Sixty patients were enrolled. The median TTP and overall survival duration were 13 and 60 weeks, respectively. One-year survival rate was 53.3%. Of the 50 patients with measurable lesion, the overall response rate was 31.7%. The most common grade 3–4 adverse event was neutropenia (61.7%). Conclusion The FLT regimen showed an efficacy comparable to other regimens of cisplatin or anthracycline combinations with the advantage of remarkably low non-hematological toxicity. These data about the efficacy of this regimen need confirmation in a phase III trial.