Fluorouracil Folinic Acid Research Articles

Adjuvant Concurrent Chemoradiotherapy (CRT) plus Docetaxel-Cisplatin-Fluorouracil (DCF) versus CRT plus Fluorouracil-Folinic Acid (FUFA) in Stage III Gastric Cancer.

Adjuvant chemoradiotherapy (CRT) is the optimal management strategy in resectable gastric cancer. There is a debate about the efficacy of more aggressive CRT plus chemotherapy regimens in adjuvant setting. This study aimed to compare the efficacy of adjuvant CRT plus docetaxel-cisplatin-fluorouracil (DCF) versus CRT plus fluorouracil-folinic acid (FUFA) in stage III gastric cancer. Patients with a diagnosis of stage III gastric cancer treated with adjuvant therapy after curative resection were analyzed. Patients' disease characteristics and impacts of the regimens on median disease-free survival (DFS) and median overall survival (OS) were analyzed retrospectively. One hundred sixty-one patients (102 in FUFA arm and 59 in DCF arm) with a median age of 56.0 (29-79) were evaluated. In the DCF arm, there were more renal toxicities (31.6% vs 6.4% P < 0.001), emergency department admissions (64.9% vs 23.7%, P < 0.001), and dose reductions/treatment modifications in the DCF arm (51.6% vs 37.2, P < 0.001). The median follow-up was 23 months (1-124) in the FUFA arm and 26.0 months (1-77) in the DCF arm. The median DFS was 25.0 months (%95 CI, 12.7-37.2) in the DCF arm and 17.0 months (%95 CI, 2.6-31.3) in the FUFA arm, P = 0.66. The median OS was 28.0 months (%95 CI, 17.0-38.9) in the DCF arm and 25.0 months (%95 CI, 11.9-36.0) in the FUFA arm, P = 0.70. In conclusion, when compared with FUFA regimen, more aggressive therapy with DCF was more toxic and did not improve OS in adjuvant setting of stage III gastric cancer.

Intratumoral stromal morphometry predicts disease recurrence but not response to 5-fluorouracil-results from the QUASAR trial of colorectal cancer.

The biological importance of tumour-associated stroma is becoming increasingly apparent, but its clinical utility remains ill-defined. For stage II/Dukes B colorectal cancer (CRC), clinical biomarkers are urgently required to direct therapeutic options. We report here prognostic/predictive analyses, and molecular associations, of stromal morphometric quantification in the Quick and Simple and Reliable (QUASAR) trial of CRC. Relative proportions of tumour epithelium (PoT) or stroma (PoS) were morphometrically quantified on digitised haematoxylin and eosin (H&E) sections derived from 1800 patients enrolled in QUASAR, which randomised 3239 (91% stage II) CRC patients between adjuvant fluorouracil/folinic acid (FUFA) chemotherapy and observation. The prognostic and predictive values of PoT/PoS measurements were determined by the use of stratified log-rank analyses. A high proportion of tumour stroma (≥50%) was associated with an increased recurrence risk: 31.3% (143/457) recurrence for ≥50% versus 21.9% (294/1343) for <50% [rate ratio (RR) 1.62; 95% confidence interval (CI) 1.30-2.02; P < 0.0001]. Of patients with stromal proportions of ≥65%, 40% (46/115) had recurrent disease within 10 years. The adverse prognostic effect of a high stromal proportion was independent of established prognostic variables, and was maintained in stage II/Dukes B patients (RR 1.62; 95% CI 1.26-2.08; P = 0.0002). KRAS mutation in the presence of a high stromal proportion augmented recurrence risk (RR 2.93; 95% CI 1.87-4.59; P = 0.0005). Stromal morphometry did not predict response to FUFA chemotherapy. Simple digital morphometry applied to a single representative H&E section identifies CRC patients with a >50% higher risk of disease recurrence. This technique can reliably partition patients into subpopulations with different risks of tumour recurrence in a simple and cost-effective manner. Further prospective validation is warranted.

Efficacy of gemcitabine plus platinum agents for biliary tract cancers

The objective of this study was to carry out a meta-analysis of the efficacy of gemcitabine+platinum agent regimens in the treatment of advanced biliary tract cancer (BTC). PubMed and Google Scholar were searched using the following combination of search terms: gemcitabine, oxaliplatin, cholangiocarcinoma, biliary, gallbladder, bile duct. Studies were eligible for inclusion in the meta-analysis if they were randomized trials on the use of gemcitabine plus a platinum agent for the treatment of advanced (unresectable or metastatic cancer) BTC. Outcomes of interest were response rate, overall survival, and progression-free survival. Pooled odds ratios/differences in median survival and 95% confidence intervals (CIs) were determined for each outcome. A total of 47 records were identified in the initial search. Ultimately, three open-label randomized trials (two phase 2 and one phase 3) met the eligibility criteria and were included in the meta-analysis. Two studies compared gemcitabine plus cisplatin with gemcitabine alone, whereas the other study compared gemcitabine plus oxaliplatin with fluorouracil-folinic acid. The total number of patients in the studies ranged from 54 to 410. The overall analyses revealed that all survival outcomes assessed were significantly more favorable for patients treated with gemcitabine plus platinum agents than for patients not treated with this combination. Response rates: odds ratio=2.639, 95% CI=1.210-5.757, Z=2.439, P=0.015; pooled difference in median overall survival=3.822 months, 95% CI=1.798-5.845 months, Z=3.702, P<0.001; pooled difference in median progression-free survival=3.268 months, 95% CI=1.996-4.541 months, Z=5.035, P<0.001. Patients with advanced BTC who are treated with gemcitabine plus platinum agents may experience better survival outcomes compared with patients who are not treated with this combination of chemotherapy.

The role of Cathepsin S as a marker of prognosis and predictor of chemotherapy benefit in adjuvant CRC: a pilot study

Background:The aim of this pilot retrospective study was to investigate the immunohistochemical expression of Cathepsin S (CatS) in three cohorts of colorectal cancer (CRC) patients (n=560).Methods:Prevalence and association with histopathological variables were assessed across all cohorts. Association with clinical outcomes was investigated in the Northern Ireland Adjuvant Chemotherapy Trial cohort (n=211), where stage II/III CRC patients were randomised between surgery-alone or surgery with adjuvant fluorouracil/folinic acid (FU/FA) treatment.Results:Greater than 95% of tumours had detectable CatS expression with significantly increased staining in tumours compared with matched normal colon (P>0.001). Increasing CatS was associated with reduced recurrence-free survival (RFS; P=0.03) among patients treated with surgery alone. Adjuvant FU/FA significantly improved RFS (hazard ratio (HR), 0.33; 95% CI, 0.12–0.89) and overall survival (OS; HR, 0.25; 95% CI, 0.08–0.81) among 36 patients with high CatS. Treatment did not benefit the 66 patients with low CatS, with a RFS HR of 1.34 (95% CI, 0.60–3.19) and OS HR of 1.33 (95% CI, 0.56–3.15). Interaction between CatS and treatment status was significant for RFS (P=0.02) and OS (P=0.04) in a multivariate model adjusted for known prognostic markers.Conclusion:These results signify that CatS may be an important prognostic biomarker and predictive of response to adjuvant FU/FA in CRC.

Determining the maximum tolerated frequency (MTF) of intraperitoneal fluorouracil/folinic acid (FU/FA) administered with adjuvant intravenous FU/FA in patients with colorectal and upper GI tumours

3668 Background: Intraperitoneal (IP) FU/FA may confer a survival advantage when added to IV adjuvant therapy in patients (pts) with colorectal cancer (Br J Cancer 77:1349, 1998). The aims of this study were to determine the MTF and pharmacokinetics (PK) of IP FU/FA when added to weekly IV FU/FA. Methods: Pts were recruited after complete resection of GI cancers where there was peritoneal involvement, after which a peritoneal port was implanted for IP treatment and PK sampling. Pts received IV FU/FA (400/20 mg/m2) weekly for 24 wks. IP FU/FA, (400/20 mg/m2) in 1500ml of 4% icodextrin, was given with increasing frequency from 4-weekly to weekly in successive cohorts, with weekly monitoring of toxicity. IP and plasma FU PK was investigated in 11 pts. Results: 57 pts were registered, of whom 53 had ports inserted. 44 (37 colorectal, 7 other) pts received 1 or more IP treatments (299 in total), but 3 withdrew early due to port failure, leaving 41 evaluable for MTF. IP FU/FA was tolerable with 4, 3 or 2-weekly IP dosing, but not with weekly dosing, with 11/13, 7/8, 10/13 and 0/7 pts respectively completing treatment without IP dose modifications. Good fluid distribution was observed by ultrasound in 41/42 pts at baseline, and in 26/27 pts after 5–13 (median 8) IP treatments. FU AUC in IP fluid was 1148 ± 567 μg/ml.hr, compared to 1.12 ± 0.61 μg/ml.hr in plasma after IP treatment alone, giving an IP/plasma ratio of >1000. Following IV and IP treatment plasma FU AUC was 11.5 ± 2.4 μg/ml.hr, with an IP/plasma ratio of 100. Systemic FU bioavailability after IP FU was 11.1 ± 6.6%. 3½ years after the end of accrual, 41% of pts have relapsed. Peritoneal relapse has occurred in 3/24 (12.5%) pts who received ≥ 7 IP doses, and in 7/20 (35%) who received ≤ 6 (χ2 p=0.06). Conclusions: The addition of IP FU/FA every 2 weeks to a standard IV regimen is safe, tolerable and practical and results in a 100-fold higher local exposure to FU than is achieved with standard IV therapy. A more reliable peritoneal administration system would improve the feasibility of this promising therapeutic approach. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ML Laboratories PLC

Determining the maximum tolerated frequency (MTF) of intraperitoneal fluorouracil/folinic acid (FU/FA) administered with adjuvant intravenous FU/FA in patients with colorectal and upper GI tumours

3668 Background: Intraperitoneal (IP) FU/FA may confer a survival advantage when added to IV adjuvant therapy in patients (pts) with colorectal cancer (Br J Cancer 77:1349, 1998). The aims of this study were to determine the MTF and pharmacokinetics (PK) of IP FU/FA when added to weekly IV FU/FA. Methods: Pts were recruited after complete resection of GI cancers where there was peritoneal involvement, after which a peritoneal port was implanted for IP treatment and PK sampling. Pts received IV FU/FA (400/20 mg/m2) weekly for 24 wks. IP FU/FA, (400/20 mg/m2) in 1500ml of 4% icodextrin, was given with increasing frequency from 4-weekly to weekly in successive cohorts, with weekly monitoring of toxicity. IP and plasma FU PK was investigated in 11 pts. Results: 57 pts were registered, of whom 53 had ports inserted. 44 (37 colorectal, 7 other) pts received 1 or more IP treatments (299 in total), but 3 withdrew early due to port failure, leaving 41 evaluable for MTF. IP FU/FA was tolerable with 4, 3 or 2-weekly IP dosing, but not with weekly dosing, with 11/13, 7/8, 10/13 and 0/7 pts respectively completing treatment without IP dose modifications. Good fluid distribution was observed by ultrasound in 41/42 pts at baseline, and in 26/27 pts after 5–13 (median 8) IP treatments. FU AUC in IP fluid was 1148 ± 567 μg/ml.hr, compared to 1.12 ± 0.61 μg/ml.hr in plasma after IP treatment alone, giving an IP/plasma ratio of >1000. Following IV and IP treatment plasma FU AUC was 11.5 ± 2.4 μg/ml.hr, with an IP/plasma ratio of 100. Systemic FU bioavailability after IP FU was 11.1 ± 6.6%. 3½ years after the end of accrual, 41% of pts have relapsed. Peritoneal relapse has occurred in 3/24 (12.5%) pts who received ≥ 7 IP doses, and in 7/20 (35%) who received ≤ 6 (χ2 p=0.06). Conclusions: The addition of IP FU/FA every 2 weeks to a standard IV regimen is safe, tolerable and practical and results in a 100-fold higher local exposure to FU than is achieved with standard IV therapy. A more reliable peritoneal administration system would improve the feasibility of this promising therapeutic approach. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ML Laboratories PLC

QUASAR: A randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients

3501 Background: The size of survival benefit from adjuvant fluorouracil/folinic acid (FUFA) CT for colorectal cancer is unclear. Methods: Patients with apparently curative resections of colon or rectal cancer were randomized following surgery between FUFA and observation (with CT considered on recurrence). CT consisted of either six 5-day, four-weekly or 30 once-weekly courses of intravenous fluorouracil (370mg/m2) with either high-dose (175mg) or low-dose (25mg) L-folinic acid, and with either levamisole or placebo. Primary outcome was all cause mortality. Results: Between June 1994 and December 2003, 3238 patients (91% Dukes B, 71% colon cancer, median age 63) from 150 centres in 17 countries were randomised. Direct randomised comparisons found no benefit for high-dose FA or levamisole (Lancet 2000;355:1588–1596). A non-randomised comparison suggested equal efficacy but less toxicity with the once-weekly schedule (Annals of Oncology 2000;11:947–955). With a median follow-up of 4.2 years, risk of death with CT vs control was 0.88 (95%CI 0.75–1.05; p=0.15) and recurrence 0.82 (0.70–0-97; p=0.02). Treatment efficacy did not differ significantly by stage, site or age but efficacy of the 4-weekly schedule was significantly (p=0.04) greater than once-weekly -a prior hypothesis. Conclusions: Chemotherapy produces a small (1% - 5%) survival benefit for stage B patients, sufficient to outweigh the inconvenience and cost for high-risk and younger patients. Longer follow-up and meta-analysis of all trials is needed to clarify the balance of benefits and disbenefits for older patients. No significant financial relationships to disclose.

QUASAR: A randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients

3501 Background: The size of survival benefit from adjuvant fluorouracil/folinic acid (FUFA) CT for colorectal cancer is unclear. Methods: Patients with apparently curative resections of colon or rectal cancer were randomized following surgery between FUFA and observation (with CT considered on recurrence). CT consisted of either six 5-day, four-weekly or 30 once-weekly courses of intravenous fluorouracil (370mg/m2) with either high-dose (175mg) or low-dose (25mg) L-folinic acid, and with either levamisole or placebo. Primary outcome was all cause mortality. Results: Between June 1994 and December 2003, 3238 patients (91% Dukes B, 71% colon cancer, median age 63) from 150 centres in 17 countries were randomised. Direct randomised comparisons found no benefit for high-dose FA or levamisole (Lancet 2000;355:1588–1596). A non-randomised comparison suggested equal efficacy but less toxicity with the once-weekly schedule (Annals of Oncology 2000;11:947–955). With a median follow-up of 4.2 years, risk of death with CT vs control was 0.88 (95%CI 0.75–1.05; p=0.15) and recurrence 0.82 (0.70–0-97; p=0.02). Treatment efficacy did not differ significantly by stage, site or age but efficacy of the 4-weekly schedule was significantly (p=0.04) greater than once-weekly -a prior hypothesis. Conclusions: Chemotherapy produces a small (1% - 5%) survival benefit for stage B patients, sufficient to outweigh the inconvenience and cost for high-risk and younger patients. Longer follow-up and meta-analysis of all trials is needed to clarify the balance of benefits and disbenefits for older patients. No significant financial relationships to disclose.

Weekly Gemcitabine plus Fluorouracil-Folinic Acid Given Weekly for Two Days in Patients with???Advanced Pancreatic Cancer

Weekly Gemcitabine plus Fluorouracil-Folinic Acid Given Weekly for Two Days in Patients with???Advanced Pancreatic Cancer

Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study

Edrecolomab is a murine monoclonal antibody to the cell-surface glycoprotein 17-1A, which is expressed on epithelial tissues and on various carcinomas. Preliminary data suggested that it might be of use in the adjuvant treatment of patients with resected stage III colon cancer. We did a randomised trial in 27 countries to determine the effect of adding edrecolomab to the combination of fluorouracil and folinic acid in these patients. After surgery, 2761 patients were randomly assigned edrecolomab plus fluorouracil-folinic acid (combination therapy [n=912]); fluorouracil-folinic acid alone (chemotherapy [n=927]); or edrecolomab alone (edrecolomab monotherapy [n=922]). Patients were assessed for survival and disease recurrence after surgery. The primary endpoint tested the hypothesis that combination therapy improved overall survival relative to chemotherapy. The key secondary endpoint was to test whether edrecolomab monotherapy was non-inferior to chemotherapy in terms of disease-free survival. Analysis was by intention to treat. Median follow-up time was 26 months (IQR 20-36). 3-year overall survival on combination therapy was no different from that on chemotherapy (74.7% vs 76.1%, hazard ratio 0.94 [95% CI 0.76-1.15], p=0.53). Disease-free survival was significantly lower on edrecolomab monotherapy than on chemotherapy (53.0% vs 65.5%, 0.62 [0.53-0.73], p<0.0001). Hypersensitivity reactions occurred in 452 (25%) patients receiving edrecolomab, causing treatment discontinuation in 71 (4%). The addition of edrecolomab to chemotherapy did not increase neutropenia, diarrhoea, or mucositis. The addition of edrecolomab to fluorouracil and folinic acid in the adjuvant treatment of resected stage III colon cancer does not improve overall or disease-free survival, and edrecolomab monotherapy is associated with significantly shorter overall and disease-free survival than fluorouracil and folinic acid and is therefore an inferior treatment option. Edrecolomab is well tolerated and its addition to fluorouracil and folinic acid does not increase the toxicity of chemotherapy.

Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

The combination of 5-fluorouracil-folinic acid and oxaliplatin has led to a significant improvement of chemotherapy efficacy in advanced pretreated colorectal cancer. The objective of the present study was, considering the oxaplatin-5-fluorouracil-folinic acid combination, to examine the impact of one given drug on the cellular determinants of cytotoxic activity of the other drug. These cellular factors were analysed on the human colon cancer cell line WiDr in clinically relevant conditions of drug exposure (‘De Gramont’ schedule) with oxaliplatin-folinic acid during 2 h followed by 5-fluorouracil 48 h. The DNA binding of oxaliplatin was significantly reduced by the presence of 5-fluorouracil but this effect was time-dependent and after 50 h the platinum incorporated into DNA was identical in controls and in the drug combination. In the presence of oxaliplatin, there was less formation of FUH2 which is the first catabolite produced in the cascade of 5-fluorouracil metabolic degradation. The effects of drugs on cell cycle were quite different from one drug to the other with oxaliplatin inducing a shift towards G2 accumulation and 5-fluorouracil-folinic acid to a greater proportion of cells in G1–S. When oxaliplatin and 5-fluorouracil-folinic acid were combined the cell cycle effects were very similar to that of the 5-fluorouracil-folinic acid sequence alone. Oxaliplatin was able to reduce thymidylate synthase activity with a marked impact 28 h after the beginning of cell exposure to the drug. The 5-fluorouracil-folinic acid drug sequence led to a profound reduction in thymidylate synthase activity and this decrease was not markedly enhanced by the presence of oxaliplatin. Regarding apoptosis, changes in mitochondrial membrane permeability were observed in the presence of the tested drugs and the impact of 5-fluorouracil-folinic acid was greater than that of oxaliplatin. The addition of oxaliplatin did not amplify the action of 5-fluorouracil-folinic acid upon mitochondrial membrane permeability change. The presence of oxaliplatin itself did not modify the intracellular concentration of total reduced folates. The fact that oxaliplatin may reduce 5-fluorouracil catabolism could be central in explaining the supra-additive interaction between these drugs.

Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

The combination of 5-fluorouracil-folinic acid and oxaliplatin has led to a significant improvement of chemotherapy efficacy in advanced pretreated colorectal cancer. The objective of the present study was, considering the oxaplatin-5-fluorouracil-folinic acid combination, to examine the impact of one given drug on the cellular determinants of cytotoxic activity of the other drug. These cellular factors were analysed on the human colon cancer cell line WiDr in clinically relevant conditions of drug exposure (‘De Gramont’ schedule) with oxaliplatin-folinic acid during 2 h followed by 5-fluorouracil 48 h. The DNA binding of oxaliplatin was significantly reduced by the presence of 5-fluorouracil but this effect was time-dependent and after 50 h the platinum incorporated into DNA was identical in controls and in the drug combination. In the presence of oxaliplatin, there was less formation of FUH2 which is the first catabolite produced in the cascade of 5-fluorouracil metabolic degradation. The effects of drugs on cell cycle were quite different from one drug to the other with oxaliplatin inducing a shift towards G2 accumulation and 5-fluorouracil-folinic acid to a greater proportion of cells in G1–S. When oxaliplatin and 5-fluorouracil-folinic acid were combined the cell cycle effects were very similar to that of the 5-fluorouracil-folinic acid sequence alone. Oxaliplatin was able to reduce thymidylate synthase activity with a marked impact 28 h after the beginning of cell exposure to the drug. The 5-fluorouracil-folinic acid drug sequence led to a profound reduction in thymidylate synthase activity and this decrease was not markedly enhanced by the presence of oxaliplatin. Regarding apoptosis, changes in mitochondrial membrane permeability were observed in the presence of the tested drugs and the impact of 5-fluorouracil-folinic acid was greater than that of oxaliplatin. The addition of oxaliplatin did not amplify the action of 5-fluorouracil-folinic acid upon mitochondrial membrane permeability change. The presence of oxaliplatin itself did not modify the intracellular concentration of total reduced folates. The fact that oxaliplatin may reduce 5-fluorouracil catabolism could be central in explaining the supra-additive interaction between these drugs.British Journal of Cancer (2002) 86, 1162–1168. DOI: 10.1038/sj/bjc/6600185 www.bjcancer.com© 2002 Cancer Research UK

Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines

A marked antitumour efficacy is currently obtained by oxaliplatin (LOHP)–fluorouracil (FU)–folinic acid (FA) combination and by CPT11–FU–FA combination. Logically, the triple association LOHP, CPT11 and FUFA will be soon tested in cancer patients. The aim of the present study was to compare two schedules combining SN38 (the active metabolite of CPT11, irinotecan) with FU–FA and LOHP. The two schedules differed by the SN38 position. The relative contribution of each drug in the resulting global cytotoxicity was evaluated. Two human colon cancer cell lines were used (WIDR and SW620 both p53 mutated). LOHP plus FA were applied for 2 h, just before a 48 h FU exposure. The SN38 sequence was applied for 24 h, starting either 48 h before LOHP-FA (schedule A), or just after LOHP-FA exposure (schedule B). Cytotoxicity was assessed by the 3-(4,5-demethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test and drug interactions were analysed according to the Chou and Talalay method, based on the computation of a combination index (CI). The SN38 position significantly induces a shift from additivity-antagonism when SN38 was applied after LOHP, towards additivity-synergism when SN38 was applied first (P = 0.03). The relative contribution (RC) of each drug in the overall cytotoxicity of the triple combination was defined as the drug concentration giving 50% cell lethality (IC 50) of the double association without that drug divided by the IC 50 of the triple association. Whatever the SN38 position, the larger contribution was made by LOHP (median RC = 2.4) and the smaller by SN38 (median RC = 1.1). In addition, the contribution of FUFA was improved when SN38 was applied first (median RC = 2.2) as compared to the opposite schedule (median RC = 1.2). Results were in agreement between the two explored cell lines. The present data should be taken into account when establishing the rationale of future trials combining CPT11, LOHP and FU–FA. © 2001 Cancer Research Campaign http://www.bjcancer.com