De Gramont Research Articles

Vinorelbine and fluorouracil plus leucovorin combination (ViFL) in patients with anthracycline and taxane-pretreated metastatic breast cancer: a phase II study

This phase II study was designed in order to evaluate efficacy and safety of the combination of vinorelbine (VNB), fluorouracil (FU) and leucovorin (LV) in patients with metastatic breast carcinoma (MBC) previously treated with anthracyclines and taxanes. From 12/2003 to 12/2007, 51 women (median age 59) were treated. Performance status (PS) (ECOG) was 0-2 (median 0). The chemotherapy consisted of VNB 25 mg/sqm on day 1 added to FU and LV (following De Gramont schedule) on day 1 and 2. Treatment was repeated every 14 days. 518 cycles of CT were administered (median 12). Most common sites of metastatic spread were: bone, liver, lymph nodes, lung. We recorded three cases of G4 neuthropenia and in one case it was febrile; no others G4 toxicities were seen. G3 toxicities were more common, especially neuthropenia (8 patients) asthenia (4) mucositis (2) and Hand-Foot Syndrome (2). Overall response rate was 27.5% (14 patients had a PR) and disease control rate was 76.5%; 12 patients experienced disease progression. Median time to progression (TTP) was 7.70 months and overall survival (OS) was 18.70 months. Results demonstrate that the ViFL regimen has substantial activity in patients with MBC already treated with anthracyclines and taxanes. The combination may be considered a valid choice for the treatment of MBC. Better survival results were seen in patients with visceral metastases than bone involvement. The low response rate shows that the ViFL regimen is not suitable for the neoadjuvant setting.

Randomized Phase III Trial Comparing Biweekly Infusional Fluorouracil/Leucovorin Alone or With Irinotecan in the Adjuvant Treatment of Stage III Colon Cancer: PETACC-3

PURPOSE The primary objective of this randomized, multicenter, phase III trial was to investigate whether the addition of irinotecan to the de Gramont infusional fluorouracil (FU)/leucovorin (LV) adjuvant regimen (LV5FU2) would improve disease-free survival (DFS) in patients with stage III colon cancer. PATIENTS AND METHODS After curatively intentioned surgery, patients with stage II and III colon cancer were randomly allocated surgery to receive LV5FU2 (LV 200 mg/m(2) as a 2-hour infusion, followed by FU; as a 400 mg/m(2) bolus and then a 600 mg/m(2) continuous infusion over 22 hours, days 1 and 2, every 2 weeks for 12 cycles: de Gramont regimen) with or without irinotecan (180 mg/m(2) as a 30- to 90-minute infusion, day 1, every 2 weeks). In total, 260 (7.9%) of 3,278 patients received an alternative high-dose infusional FU/LV regimen (Arbeitsgemeinschaft Internische Onkologie regimen) with or without irinotecan. Results The principal efficacy analysis was based on 2,094 treated patients with stage III disease, randomly allocated in the LV5FU2 strata. After a median follow-up of 66.3 months, the 5-year DFS rate was 56.7% with irinotecan/LV5FU2 and 54.3% with LV5FU2 alone (primary end point: log-rank P = .106). Combining irinotecan with LV5FU2 did not significantly improve overall survival in this patient group compared with LV5FU2 alone (5-year rate 73.6% v 71.3%, respectively; log-rank P = .094). The addition of irinotecan to LV5FU2 was associated with an increased incidence of grade 3 to 4 GI events and neutropenia. CONCLUSION Irinotecan added to LV5FU2 as adjuvant therapy did not confer a statistically significant improvement in DFS or overall survival in patients with stage III colon cancer compared with LV5FU2 alone.

Use of two-year disease-free survival (DFS) as a primary endpoint in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: New data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, NSAPB C-06 and C-07, and C89803

4011 Background: The ACCENT group previously validated DFS with 3 years (yr) median follow-up (f-up) based on 20,898 pts from trials testing 5-FU based regimens (rx) (3yr DFS) as an endpoint to predict overall survival with 5 yr median f-up (5yr OS) (Sargent, JCO 2005). ACCENT further proposed (1) 2yr DFS predicts 5yr OS, (2) a stronger relationship between DFS and OS in stage III pts (Sargent JCO 2007) and (3) 6 or 7 yrs are necessary to demonstrate DFS and OS association in future trials due to extended survival following recurrence (de Gramont ASCO 2008). The relationship between endpoints in more recent trials with oral fluoropyrimidines, oxaliplatin, and irinotecan is unknown. Methods: Concordance between 2 and 3yr DFS, and 5 and 6yr OS was examined in 6 randomized phase III trials from 1997–2002. Individual data for 12,676 pts was analyzed; 2 trials tested oxaliplatin, 2 irinotecan, and 2 oral rx vs 5-FU/LV control. Association between DFS and OS hazard ratios (HRs) via weighted least squares (WLS), and concordance between predicted and actual within-trial HRs, were calculated overall and for stage III pts. Results: Overall association between 3 yr DFS and 5 yr OS HRs was reduced compared to the prior ACCENT analysis (Table). In stage III pts, the association between DFS and OS HRs remained strong. Observed 5 and 6yr OS HRs were predicted accurately by 2yr DFS overall and in stage III pts (within 95% prediction limits in all trials). In all pts, DFS HRs were more highly associated with 6 vs 5yr OS HRs. Conclusions: In recent trials in stage III pts, DFS HRs based on 2yr median f-up are highly predictive of 5 and 6yr OS HRs. In all pts the association between DFS and OS HRs is stronger for 6yr OS, but 7yr follow-up may be required. These data support 3yr DFS as a primary endpoint for modern stage III trials, and indicate that 2yr DFS would also be an appropriate primary endpoint. [Table: see text] [Table: see text]

A phase I clinical trial of vorinostat in combination with sFULV2 in patients with refractory solid tumors

4083 Background: Thymidylate synthase (TS) over-expression is associated with 5-FU resistance. Pre-clinical studies demonstrate that vorinostat down-regulates intra-tumor TS in a dose-dependent fashion and augments 5-FU antitumor activity in xenograft models. We conducted a phase I clinical trial of an intermittent schedule of QD x 3 vorinostat in combination with a fixed dose of fluorouracil (5-FU) and leucovorin (LV) in patients (pts) with refractory solid tumors. Methods: Vorinostat was escalated in a standard 3 x 3 design in combination with a fixed dose of 5-FU and LV (simplified de Gramont regimen, sFULV2). Vorinostat was given QD x 3 on an every-2-week cycle. sFULV2 started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hrs followed by 5-FU 400 mg/m2 bolus and 5-FU 2400 mg/m2 over 46 hrs. Results: 24 pts were enrolled: Male/Female: 11/13; ECOG 0/1: 6/18; Age: median 60 (range 42–77) yrs. 21 pts had colorectal cancer (CRC), 1 had gastric, 1 had esophageal, and 1 had anal cancer. Vorinostat dose-levels (DL) were 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1700 mg, and 2000 mg. Dose-limiting toxicities (DLT), consisting of fatigue and hand-and-foot syndrome (H&F), were seen in 2 of 3 pts at the 2000 mg DL. None of the 6 pts at the 1700 mg DL had a DLT. Cycle 1 grade 3/4 toxicities consisted of thrombocytopenia, GI bleeding, fatigue, and H&F in 2 pts at the 2000 mg DL and a non-DLT G3 diarrhea (lasted <24 hrs) in 1 pt at the 1700 mg DL. Grade 2 nausea, fatigue, and anorexia were common; especially at DL ≥ 1700 mg. Antitumor activity was noted in pts with CRC despite prior refractoriness to 5-FU and failure to oxaliplatin, irinotecan, and cetuximab in all pts. 12/21 CRC pts had a confirmed SD (11) or PR (1). CRC pts had a median PFS of 4 months, a ≥ 6 months PFS rate of 43%, and a ≥ 8 months PFS rate of 33%. Conclusions: The maximum tolerated dose (MTD) of vorinostat in combination with sFULV2 is 1700 mg PO QD x 3 every 2 weeks. This combination is associated with considerable activity in pts with 5-FU-refractory CRC and warrants further investigation. An expanded MTD cohort is accruing to investigate 5-FU-vorinostat PK interaction and intra-tumor TS down-regulation. (This work was supported by a grant from CTEP and the ACS.) No significant financial relationships to disclose.

Oxaliplatin or Irinotecan As Adjuvant Therapy for Colon Cancer: The Results Are In

Oxaliplatin or Irinotecan As Adjuvant Therapy for Colon Cancer: The Results Are In

Increased soluble urokinase plasminogen activator receptor (suPAR) is associated with thrombosis and inhibition of plasmin generation in paroxysmal nocturnal hemoglobinuria (PNH) patients

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired genetic disorder of the bone marrow that produces intravascular hemolysis, proclivity to venous thrombosis, and hematopoietic failure. Mutation in the PIG-A gene of a hematopoietic stem cell abrogates synthesis of glycosylphosphoinositol (GPI) anchors and expression of all GPI-anchored proteins on the surface of progeny erythrocytes, leukocytes, and platelets. Urokinase plasminogen activator receptor (uPAR), a GPI-linked protein expressed on neutrophils, mediates endogenous thrombolysis through a urokinase-dependent mechanism. Here we show that membrane GPI-anchored uPAR is decreased or absent on granulocytes and platelets of patients with PNH, while soluble uPAR (suPAR) levels are increased in patients' plasma. Serum suPAR concentrations correlated with the number of GPI-negative neutrophils and were highest in patients who later develop thrombosis. In vitro, suPAR is released from PNH hematopoietic cells and from platelets upon activation, suggesting that these cells are the probable source of plasma suPAR in the absence of GPI anchor synthesis and trafficking of uPAR to the cell membrane. In vitro, the addition of recombinant suPAR results in a dose-dependent decrease in the activity of single-chain urokinase. We hypothesized that suPAR, prevents the interaction of urokinase with membrane-anchored uPAR on residual normal cells.

Cytotoxic chemotherapy for incurable colorectal cancer: living with a PICC‐line

(i) To determine which aspects of living with a peripherally inserted central catheter (PICC) line cause Modified de Gramont (MdG) patients most difficulty. (ii) To explore MdG patients' views of the PICC-line experience. (iii) To determine if patients view PICC-lines as a benefit or a burden when receiving ambulatory MdG chemotherapy. A two-stage, descriptive study. Phase 1 comprised semi-structured interviews. Phase 2 surveyed the MdG population. Phase 1 interview data informed the Phase 2 questionnaire. The setting was a West of Scotland Cancer Care Centre and the sample was: Phase 1, a convenience sample of 10 MdG patients; Phase 2, 62 consecutive patients. A response rate of 93.9% for Phase 2. The majority of PICC-line patients held favourable views towards having a PICC-line and adapted well with minimal disruption to daily life. Concerns were evident regarding coping at home with a PICC-line, chemotherapy spillage, dealing with complex information and the responsibility of patients/carers regarding PICC-line management. Patients preferred ambulatory chemotherapy to in-patient treatment. PICC-lines should be considered for more chemotherapy patients but service development is necessary to ensure individual needs are addressed. Contributes to the PICC-line literature by providing a national patient perspective on a range of daily living activities (DLAs). PICC-line patients prefer out-patient ambulatory chemotherapy rather than in-patient treatment. The longer a patient has a PICC-line, the more able they are to manage activities such as dressing. Concerns remain over chemotherapy spillage, partner/carer responsibility for PICC-line maintenance and the proper balance between required information and what the patient wants to know.

Sinusoidal obstruction syndrome (veno-occlusive disease) in a patient receiving bevacizumab for metastatic colorectal cancer: a case report

IntroductionWe present the case of a patient with colon cancer who, while receiving bevacizumab, developed sinusoidal obstruction syndrome (veno-occlusive disease) (SOSVOD). Certain antitumour agents such as 6-mercaptopurine and 6-thioguanine have also been reported to initiate hepatic SOSVOD in isolated cases. There have been no reports so far correlating bevacizumab with SOSVOD.Case presentationA 77-year-old man was being treated with oxaliplatin and a modified de Gramont regimen of 5-fluorouracil for metastatic colon cancer. Bevacizumab (7.5 mg/kg) was added from the seventh cycle onwards. Protracted neutropenia and thrombocytopenia led to discontinuation of oxaliplatin after the ninth cycle. A computed tomography scan showed complete response and bevacizumab was continued for another 3 months, after which time the patient developed right hypochondrial pain, transudative ascites, splenomegaly and abnormal liver function tests. Upper gastrointestinal endoscopy showed oesophageal varices. Liver biopsy showed features considered to be consistent with SOSVOD. Bevacizumab was stopped and a policy of watchful waiting was adopted. He tolerated the acute damage to his liver and subsequently the ascites resolved and liver function tests normalised.ConclusionWe need to be aware that bevacizumab can cause sinusoidal obstruction syndrome (veno-occlusive disease) and that the occurrence of ascites should not be attributed to progressive disease without appropriate evaluation.

Preferences of Patients with Advanced Colorectal Cancer for Treatment with Oral or Intravenous Chemotherapy

In recent years, patient-reported outcomes such as health-related quality of life have become important areas of clinician focus in general cancer management. Patients' preferences for, and/or satisfaction with, oral versus intravenous (IV) chemotherapy schedules may have a major impact on such outcomes. To evaluate preferences for oral or IV chemotherapy in patients with advanced colorectal cancer. A multicenter, randomized, crossover trial was conducted in 12 hospitals in Southern Italy, in which 22 patients with advanced colorectal cancer received one cycle of oral capecitabine ± irinotecan or oxaliplatin, followed by one cycle of an IV de Gramont or similar regimen (arm A), or the same regimens in reverse order (arm B). Patients were aged 50-70years and 21% had a higher level of education (graduate or similar). Patients received oral capecitabine 3500mg/m/day for 7days (± irinotecan 180mg/m or oxaliplatin 85mg/m on day1 only), followed by an IV de Gramont regimen ± irinotecan (FOLFIRI) or oxaliplatin (FOLFOX); or the two schedules administered in reverse order.The main outcome measure was patients' preferences for oral versus IV chemotherapy, as determined by a pre- and post-treatment therapy preference questionnaire (TPQ). Before treatment, 75% of patients preferred oral therapy. Characteristics that patients considered to be important were that treatment should not interfere with daily activities (100% of patients) and should not cause fatigue (95%), diarrhea (76%), or painful mouth ulcers (76%); other factors considered important were the risk of infection and nausea (90%), and that treatment could be administered at home (65%). After receiving both chemotherapy schedules, only 45% of patients preferred oral therapy, while 55% preferred IV therapy. Among the latter, the most important characteristics influencing treatment choice were less nausea (66%), fewer mood effects (65%), the safety of hospital IV treatment (62%), less interference with family relationships (55%), less vomiting (55%), less interference with daily activities (50%), and less diarrhea (50%). Although the order in which patients received therapy did not influence treatment preference, significantly fewer patients with a lower rather than higher educational level preferred oral therapy (47% vs 80%; chi-square test = 9.9; p = 0.002). These results suggest that there may be a correlation between educational level and the preference of patients with advanced colorectal cancer for oral or IV chemotherapy.

Ambulatory 2 hours infusion of 5-FU modulated by low-dose leucovorin in the palliative treatment of advanced epithelial cancer patients with low performance status

20600 Background: In the context of palliative care, when clinically indicated for symptomatic control, chemotherapy regimens should ideally offer a fair chance of anticancer activity and clinical benefit, be feasible with a simple method of administration and have a favorable toxicity profile. We evaluated, in a cohort of advanced epithelial cancer patients, most of them already treated with multiple previous lines of chemotherapy, an adaptation of the active and well tolerated ‘de Gramont‘ regimen. Methods: Patients (pts) with histologically proven advanced epithelial neoplasms, adequate bone marrow, hepatic and renal function, ECOG status ≤ 3, were treated with EV bolus leucovorin 20 mg\/m2 D1 and D2 + 5-FU 400 mg\/m2 EV bolus D1 and D2 + a two-hours infusion of 5-FU 600 mg\/m2 D1 and D2, every two weeks. Results: Twenty pts (17 females, 3 males; mean age 54,5 years, range 44–76), with a mean of 2,3 previous lines of chemotherapy (range 0–6), received a total of 155 cycles (mean of 7 cycles/patient, range 3–19), of the adapted de Gramont regimen. The primary tumors were: breast (10 PTS), gastro-intestinal (6 PTS), ovary (2 PTS), head and neck (1 patient), unknown primary carcinoma (1 patient). The ECOG status of the pts was as follows: ECOG 1 (3 pts), ECOG 2 (12 pts), and ECOG 3 (5 pts), mean of 2,1. The partial response rate was 28% (95% CI: 8–48); 8 patients (38%) demonstrated stable disease and 1 patient had a complete response. Clinical benefit with improved performance status and/or decrease in pain was noted in 16 pts. The median time to progression was 24 weeks (95% CI: 16 - 32), and the mean overall survival was 36 weeks. No grade 4 toxicities were detected and grade 3 toxicities were as follows: leucopenia (3 pts) and anemia (1 patient). Common grade 1/2 toxicities were: hand-foot syndrome (4 pts), anemia (6 pts), mucositis (6 pts), diarrhea (6 pts), conjunctivitis (1 patient). The toxicities were managed with 20% dose reductions and/or chemotherapy delays. Overall, dose reductions occurred in 9 patients and chemotherapy delays in 13 patients. Conclusions: The adapted de Gramont Regimen, as described, is well tolerated and active in the palliative setting of patients with advanced epithelial cancer and low ECOG performance status. No significant financial relationships to disclose.

Pharmacokinetics of irinotecan: Comparison of intravenous and intra-arterial administration in patients with liver metastases

14608 Background: To determine and to compare the plasma pharmacokinetics of irinotecan when administered intravenously and in hepatic artery to the same patient with liver metastases; to evaluate the toxicity of both kinds of infusion. Methods: In 10 enrolled patients, plasma levels of irinotecan and its metabolites SN-38 and SN-38 glucuronide were measured by HPLC after a loco-regional and a systemic infusion, and main pharmacokinetic parameters were calculated, including area under the time-concentration curve (AUC) and clearance. Irinotecan infusion was followed by De Gramont regimen given systemically (folinic acid, 5-fluorouracil bolus and continuous infusion). Results: The pharmacokinetic data provided evidence that the intra-arterial (IA) infusion increased the conversion of irinotecan to SN-38 with respect to standard intra-venous (IV) infusion. In fact, the AUC of irinotecan, SN-38 and SN-38 glucuronide were 5462.2±696.7, 87.5±29.9 and 904.7±150.9 h×ng/ml, respectively, after IA administration, and 6799.2±1055.7, 60.9±24.1 and 460.8±136.1 h×ng/ml, respectively, for IV infusion. The IA infusion was characterized by lower biliary index and greater glucuronidation ratio and relative extent of conversion than the IV administration, despite a more frequent occurrence of moderate-to- severe toxicity after IA infusion. Nine heavily pretreated patients who received at least 2 cycles were evaluable for response, and we observed 4 stable disease and 5 progressions. Conclusions: The comparison of the IA and IV infusion of irinotecan in the same patient demonstrates that the IA route improves the transformation of irinotecan to SN-38 and also results in increased glucuronidation of the active metabolite. Then, the administration of irinotecan as a IA infusion is feasible despite higher incidence of toxicity in comparison to IV infusion. No significant financial relationships to disclose.

A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer

BackgroundTo compare irinotecan with the Nordic 5-fluorouracil (5-FU) and folinic acid (FA) bolus schedule [irinotecan 180 mg/m2 on day 1, 5-FU 500 mg/m2 and FA 60 mg/m2 on day 1 and 2 (FLIRI)] or the Lv5FU2 schedule [irinotecan 180 mg/m2 on day 1, FA 200 mg/m2, 5-FU bolus 400 mg/m2 and infused 5-FU 600 mg/m2 on day 1 and 2 (Lv5FU2-IRI)] due to uncertainties about how to administrate 5-FU with irinotecan. Patients and methodsPatients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS). ResultsPatient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%. ConclusionsIrinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated.

XELOX compared to FOLFOX4: Survival and response results from XELOX-1/ NO16966, a randomized phase III trial of first-line treatment for patients with metastatic colorectal cancer (MCRC)

4030 Background: In a phase II study in untreated MCRC patients, XELOX (capecitabine + oxaliplatin) appeared to have similar efficacy compared with previously published FOLFOX4 data [1]. We therefore started a phase III 2-arm open-label non-inferiority study comparing XELOX with FOLFOX4. In 2003 the addition of bevacizumab (Bev) to irinotecan/5-FU/LV was shown to improve progression-free survival (PFS) and overall survival [2]. We then amended our trial to a 2x2 partially blinded study to assess the addition of Bev. Methods: Original 2-arm study: XELOX (oxaliplatin 130 mg/m2 iv, capecitabine 1,000 mg/m2 bid oral d1- 14, q3w) vs. FOLFOX4 (oxaliplatin, 5-FU, leucovorin as described previously) [3]. In August 2003, amended to 2x2 partially blinded study: by adding Bev 7.5 mg/kg iv q3w or placebo (Pla) to XELOX and Bev 5 mg/kg iv q2w or Pla to FOLFOX4. Results: The original 2-arm study recruited 634 pts; after transition to 2x2, an additional 1400 patients were recruited. We previously reported non-inferiority in terms of PFS of XELOX vs. FOLFOX4 for the whole study population [4]. With 404 events, the overall survival data from the original 2-arm study are mature and show a HR for XELOX vs. FOLFOX4 of 0.93 (97.5% CI, 0.74–1.16). The response rates by investigator and independent review for the whole study population are shown in the table . Conclusions: XELOX is non-inferior to FOLFOX4. Overall survival data for the whole 2034 patient study population will be presented at the meeting. *no response assessment. 1. Cassidy J et al. J Clin Oncol 2004;22:2084–91. 2. Hurwitz H et al. N Eng J Med 2004;350:2335–42 3. De Gramont A et al. J Clin Oncol 2000;18:2938–47. 4. Cassidy J et al. Ann Oncol 2006;17(Suppl. 9):LBA3. [Table: see text] [Table: see text]

Efficacy and safety of irinotecan-based chemotherapy in poor risk patients suffering from metastatic colorectal cancer

14581 Background: Irinotecan (CPT11) combination chemotherapy has provided a significant advancement in the management of patients with metastatic colorectal cancer (MCRC). However, there was some data indicating that poor risk cases might not benefit from longer survival with CPT11-based chemotherapy, mainly due to higher regimen toxicity. Purpose: To evaluate the hypothesis, whether CPT-11- based chemotherapy can produce similar TTP and OS in a group of poor risk MCRC patients in comparison to standard risk MCRC cases. Patients and Methods: Out of 170 CRC patients treated in our departments between 2002 - 2006, 36 poor risk MCRC patients (poor risk group was defined as 2 or more criteria being fulfilled, i.e. PS >1, and/or elevated serum LDH, and/or >1 metastatic site, and/or prior adjuvant chemotherapy), were chosen for this analysis and compared retrospectively with our standard risk MCRC cases. The poor risk arm consisted of 9 females and 27 males, in age between 40–76 [median 63,5]. All the patients were treated with CPT11-based chemotherapy, according to either AIO or de Gramont regimen. Results: In the analyzed poor risk group the confirmed RR (CR+PR) after six months of the treatment was 25,0% what was much lower than in standard risk group (RR = 40%), however did not reach the statistical significance; additional 52,8% of patients achieved SD; 8 patients (22,2%) progressed during therapy. The median TTP was 9 months and the median OS was 15 months, what were not statistically different from the standard risk group; 2-year survival obtained 27,8% of patients. No grade (G) 4 toxicity was observed. The most common adverse events (AE) were diarrhea [25% - 9 pts] and neutropenia [11.1% - 4 pts], but G3 AE were noted only in 2 and 1 person respectively. Conclusions: This analysis showed, that CPT11-based chemotherapy is an effective and safe treatment option even for poor risk patients suffering from MCRC. Although the RR was lower in comparison to standard risk cases it did not translate into shorter TTP as well as OS. Similar to ours results were published in various scientific papers. To define a precise role of various optimization strategies of CPT11-based chemotherapy in MCRC, randomized prospective multicenter studies are mandatory. No significant financial relationships to disclose.

5-Fluorouracil increases the number and complexity of premature complexes in the heart: a prospective study using ambulatory ECG monitoring

The cardiac toxicity of LV5FU2 (de Gramont) regimen which is a widely used chemotherapy regimen in gastrointestinal system cancers is not well defined. We aimed to evaluate the impact of this regimen on cardiac rhythm. Two Holter ECG recordings were obtained in all patients with gastrointestinal system cancers treated with LV5FU2 regimen as first-line chemotherapy (one before and the second during the first 24 h of chemotherapy). Records were reviewed for the heart rate, rhythm, atrial premature complexes (APC), ventricular premature complexes (VPC), grades according to Lown-Wolf grading system and ST segment changes. Holter ECG recordings were evaluated in 27 patients. In the baseline evaluation, neither clinical symptom nor ST segment changes were observed. During the treatment period, chest pain was observed in two patients without any cardiac enzyme and ST segment changes. Moreover, a decrease in mean heart rate, and an increase in the number and complexity of premature complexes secondary to treatment were observed. The mean heart rate, APC per hour and VPC per hour (+/-SD) before vs. during treatment were, respectively, 93.1+/-16.4 vs. 81.6+/-12.7 (p=0.001), 18.9+/-54.0 vs. 45.3+/-53.8 vs. (p=0.049) and 12.7+/-29.6 vs. 38.1+/-42.1 (p=0.002). LV5FU2 regimen leads to a decrease in mean heart rate and a significant increase in APC and VPC which may lead to serious arrhythmias. These effects must be better understood for a safer administration of this useful and widely used drug regimen.

Cost-Effectiveness Analysis of First-Line Chemotherapies in Metastatic Colorectal Cancer

Background: The De Gramont regimen (or high-dose LV5FU2, HD-LV5FU2) is considered a standard treatment for metastatic colorectal cancer. The aim of the study was to evaluate the efficacy and the costs of three regimens as compared to HD-LV5FU2: raltitrexed (R), LV5FU2 with a lower dose of folinic acid (LD-LV5FU2), and weekly infusional 5FU (WI-FU). Methods: An economic analysis was performed prospectively as part of a randomized trial comparing first-line chemotherapy regimens in 294 patients with unresectable metastatic colorectal cancer. The primary endpoint was event-free survival (EFS). Direct medical costs were computed from the health system viewpoint using 2001 unit costs. Results: None of the three regimens improved EFS as compared to HD-LV5FU2. R was less effective and more toxic. The mean total cost per patient was € 15,970 for HD-LV5FU2. The cost of R (€ 10,687) was lower than that of HD-LV5FU2 (p = 0.008). The cost of LD-LV5FU2 (€ 14,888) and of WI-FU (€ 13,760) was not significantly different from that of HD-LV5FU2. Conclusion: The lower efficacy and increased toxicity of R made it a clinically inferior regimen despite its easy administration and lower cost. The HD-LV5FU2 protocol remains a better treatment. LD-LV5FU2 appeared a good alternative regimen because it reduced costs without jeopardizing its efficacy. The WI-FU regimen did not show a significant difference in terms of efficacy, but suggested toxicity to be slightly increased.

A randomised phase II study of OSI-7904L versus 5-fluorouracil (FU)/leucovorin (LV) as first-line treatment in patients with advanced biliary cancers

The prognosis of advanced biliary tract carcinoma is poor with chemotherapy limited to a palliative role. This randomised study was designed to evaluate the effectiveness of a new liposomal thymidylate synthase inhibitor (TSI), OSI-7904L, in parallel with a modified de Gramont regimen of 5-FU/LV in patients with advanced biliary cancer. Patients with previously untreated advanced or metastatic carcinoma of the biliary tract were randomised to receive either OSI-7904L 12 mg/m2 intravenously every 21 days or a modified de Gramont schedule of 5-FU/LV (intravenous l-LV 200 mg/m2, bolus 5-FU 400 mg/m2 and a 46-h infusion of 5-FU 2,400 mg/m2) every 14 days. Twenty-two patients were randomised, 11 to each group. No patients responded in the OSI-7904L arm, while one patient achieved a partial response in the 5-FU/LV arm. The rates of disease stabilisation were 4/11 (OSI-7904L) and 10/11 (5-FU/LV). Both treatment arms were generally well tolerated. These results show that the activity of OSI-7904L is below a level of clinical relevance in advanced biliary tract cancer, providing only a small degree of disease stabilisation. A simplified de Gramont schedule appears to have marginally more activity. Both treatments were well tolerated.

The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation

To assess the clinical and cost-effectiveness of oxaliplatin in combination with 5-fluorouracil/leucovorin (5-FU/LV), and capecitabine monotherapy (within their licensed indications), as adjuvant therapies in the treatment of patients with Stage III (Dukes' C) colon cancer after complete surgical resection of the primary tumour, as compared with adjuvant chemotherapy with an established fluorouracil-containing regimen. Ten electronic bibliographic databases were searched from inception to January 2005. Searches were supplemented by hand searching relevant articles, sponsor and other submissions of evidence to the National Institute of Health and Clinical Excellence and conference proceedings. A systematic review and meta-analysis (where appropriate) of clinical efficacy evidence and a cost-effectiveness review and economic modelling were carried out. Marginal costs, life years gained and cost-effectiveness acceptability curves were estimated. Probabilistic sensitivity analysis was used to generate information on the likelihood that each of the interventions was optimal. Three randomised active-controlled trials, of varying methodological quality, were included in the review. The MOSAIC trial and NSABP C-07 study considered the addition of oxaliplatin to adjuvant treatment (albeit administered in different 5-FU/LV regimens) and the X-ACT study compared oral capecitabine with bolus 5-FU/LV alone. A review of the available evidence indicated that in patients with Stage III colon cancer, oxaliplatin in combination with an infusional de Gramont schedule of 5-FU/LV (FOLFOX4) was more effective in preventing and delaying disease recurrence than infusional 5-FU/LV alone (de Gramont regimen). Serious adverse events and treatment discontinuations due to toxicity were more evident with oxaliplatin-based regimens (FOLFOX4 and FLOX regimen) than infusional or bolus 5-FU/LV alone (de Gramont and Roswell Park regimen). Oral capecitabine was at least equivalent in disease-free survival to the bolus Mayo Clinic 5-FU/LV regimen for patients with resected Stage III colon cancer. Although, the safety and tolerability profile of capecitabine was superior to that of the Mayo Clinic 5-FU/LV regimen, it has not been evaluated in comparison with other less toxic 5-FU/LV regimens currently in common use in the UK. Based on the assumptions and survival analysis methods used, the cost-effectiveness analysis using economic modelling estimated that capecitabine was a dominating strategy and resulted in a cost-saving of approximately pound 3320 per patient in comparison with the Mayo Clinic 5-FU/LV regimen, while also providing an additional 0.98 quality-adjusted life-years (QALYs) over a 50-year model time horizon. Oxaliplatin in combination with 5-FU/LV (FOLFOX4 regimen) is estimated to cost an additional pound 2970 per QALY gained when compared with the de Gramont 5-FU/LV regimen and demonstrated superior survival outcomes with marginal costs. The uncertainty analysis suggests that both interventions have a high probability of being cost-effective at a threshold of both pound 20,000 and pound 30,000. An indirect comparison of the FOLFOX4 and Mayo Clinic 5-FU/LV regimens suggests that the use of FOLFOX4 in place of the Mayo Clinic 5-FU/LV regimen would cost an additional pound 5777 per QALY gained. An incremental cost-effectiveness ratio (ICER) is estimated to be approximately pound 13,000 per QALY gained from treatment with FOLFOX4 compared with capecitabine. However, if the Mayo Clinic and the de Gramont 5-FU/LV regimens are assumed to be equivalent in terms of effectiveness, the ICER of FOLFOX4 in comparison with capecitabine may be greater than pound 30,000 per QALY. The evidence suggests that both capecitabine and FOLFOX4 are clinically effective and cost-effective in comparison with 5-FU/LV regimens (Mayo Clinic and de Gramont schedules). Further research is suggested into the effectiveness, tolerability, patient acceptability and costs of different oxaliplatin/fluoropyrimidine schedules in the adjuvant setting; the effects of treatment duration on efficacy; adverse events; resource data collection strategies and reporting of summary statistics; subgroups benefiting most from adjuvant chemotherapy; and methods for estimating mean survival.

Tolerability of FOLFOX4 adjuvant treatment – our experiences in the first year

Purpose: In Hungary, we have the opportunity to use oxaliplatin in the adjuvant treatment of stage III colorectal cancer (CRC) since autumn of 2004. This drug is a highly effective anticancer agent, but administering in adjuvant setting it is important to know its safety profile. In a 15-month period, between November 2004 and January 2006 we evaluated the gastrointestinal, haematological, neurological and other types of toxicity of the adjuvant FOLFOX4 (oxaliplatin + de Gramont) cytostatic treatment at our department.

Cost-effectiveness of adjuvant capecitabine, Mayo Clinic and de Gramont regimens for stage III colon cancer in the French setting

13506 Background: The oral fluoropyrimidine capecitabine is as effective but better tolerated than i.v. 5-FU/LV as first-line treatment in patients (pts) with metastatic colorectal cancer. Costs associated with the administration route could vary widely according to national rules and medical practice. We compared costs and outcomes of capecitabine, the Mayo Clinic, and de Gramont regimens as adjuvant treatment for stage III colon cancer. Methods: We assessed the cost-effectiveness of the three regimens using the third-party payer perspective, time horizon and efficacy/safety data (adjusted for indirect comparisons) from two published clinical trials [Twelves et al. N Engl J Med 2005; Andre et al. J Clin Oncol 2003]. The costs of chemotherapy and the treatment of side effects were estimated from the clinical trials and expert opinion. We applied French standard costs to resources consumed and evaluated cost-effectiveness using relapse-free survival (RFS), defined in X-ACT study, as an efficacy indicator. One-way sensitivity analyses were performed varying the cost estimates for each treatment. Results: Capecitabine-treated pts had a mean life duration increase without treatment failure of 1.3 months vs. Mayo (see table). De Gramont was considered as effective as Mayo. In the base-case analysis capecitabine appeared to be dominant, more effective and less costly than either Mayo Clinic or de Gramont. In the sensitivity analyses, capecitabine remained dominant except for the minimum costs scenario vs. de Gramont. In this case, the cost-effectiveness ratio was estimated at 8997.55€ per year without relapse. Conclusions: As adjuvant treatment for colon cancer, capecitabine decreases medical resources consumed, mainly in hospitals. Its approval in this setting is expected to bring cost savings and better outcomes. [Table: see text] [Table: see text]