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PURPOSE A phase II trial was designed to determine the efficacy and the tolerance of interleukin-2 (IL-2), interferon alfa-2a (IFNalpha), and fluorouracil (5-FU) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS One hundred eleven patients were included. Patients received subcutaneous IL-2 9 x 10(6) IU daily for 6 days and IFNalpha 6 x 10(6) IU on days 1, 3, and 5 every other week for 8 weeks. 5-FU was administered through a continuous infusion at 600 mg/m2 for 5 consecutive days for 1 week every 4 weeks. RESULTS The response rate was 1.8% (95% confidence interval [CI], 0% to 4.3%) with only two partial responses (PRs). Toxicity was moderate with 3.6% grade 4 events and two deaths related to treatment. CONCLUSION This regimen of IL-2, IFNalpha, and 5-FU in patients with metastatic renal cell carcinoma was ineffective. The results raise the question of the dose and schedule of subcutaneous cytokines that must be used in metastatic renal carcinoma.

3533 Background: PFS has previously been established as a surrogate for OS based on IPD from first-line mCRC trials conducted before 1999. As mCRC treatment (trt) has advanced in the last decade and OS has increased from 1 to 2 years, this surrogacy required re-examination. Methods: IPD from 16,762 pts, median age 62, 62% male, 53% ECOG PS 0 were available from 22 1st line mCRC studies conducted from 1997-2006; 12 tested targeted (anti-angiogenic and/or anti-EGFR) regimens. The relationship between PFS (first event of progression or death) and OS was evaluated at patient-, trt-arm-, and trial-levels using correlation (corr.) coefficients and R2 (closer to 1 the better) from weighted least square (WLS) regression of arm-specific survival rates and trial-specific hazard ratios (HRs), estimated using Cox and Copula bivariate models. The concordance of significance (CoS) of the treatment effects (TEs) on both endpoints was calculated. Results: 44% pts received a targeted regimen. Median PFS was 8 and OS was18 months. The corr. between PFS and OS was modest at all three levels with low CoS in TE comparisons (see Table). Analyses limited to trials testing targeted trts, non-strategy trials, or superiority trials did not improve surrogacy. Conclusions: In modern mCRC trials, where survival post-first progression exceeds time to first progression, PFS TEs do not reliably predict TEs on OS. Nonetheless, until alternative endpoints of clinical benefit can be validated, PFS remains a relevant primary endpoint for 1st line mCRC trials, as our data demonstrate that the ability for any agent to produce an OS benefit from a single line of therapy is challenging. [Table: see text]

3510^ Background: The primary analysis of PRIME demonstrated that pmab + FOLFOX4 significantly improved progression-free survival (PFS) vs FOLFOX4 for 1st line mCRC in patients (pts) with wild-type...

3567^ Background: Pmab is a fully human anti epidermal growth factor receptor (EGFR) monoclonal antibody. The primary analysis of this study (PRIME) demonstrated that pmab + FOLFOX4 significantly i...

595 Background: Metastatic colorectal cancer (mCRC) management has been clearly improved by targeted therapies such as anti VEGF and /or anti-HER1 drugs. The evaluation of the use of targeted therapies in the real world is strategic to assess health politics. OMIT Bretagne-Pays de la Loire is a network of private and public cancer centers that has been leading cohort studies evaluating Folfiri-bevacizumab treatment, the cost of targeted therapies and the succession of targeted therapies. Methods: The purpose of this study is to evaluate the benefit and safety of three consecutive targeted therapies in patients with KRAS wild-type unresectable mCRC. Sex, age, localization of the primary tumor site, successive chemotherapeutic regimens, toxicities, response rates, progression free survival and overall survival have been studied. Results: 34 patients (22 men, 12 women, median age 63 years [43-82]) have been prospectively recruited between 2003 and 2010. All of them received bevacizumab specially in association with FOLFIRI, cetuximab in association with irinotecan, panitumumab as monotherapy and others chemotherapies than FOLFOX, FOLFIRI, XELOX. The primary tumor site was colon (71%), junction (5%), and rectum (24%). 22 patients had metastatic colorectal tumor, 28 were operated on their primary tumor and 12 underwent resection after one line of treatment. Patients received successively 3 to 8 different lines of treatment for progressive mCRC. Toxicities of targeted therapies were manageable. Objective responses were observed in 38% (13) of the patients treated with BBR, 37% (11) treated with CBR and 25% (6) treated with P. Disease stabilization was achieved in 32% (11) of the patients treated with BBR, in 10% (3) with CBR and in 8% (2) with P. PFS at 80 months is 15%. Median OS from first metastatic line at death was 47.43 months (24.23-70.84). PFS and OS curves will be shown during the meeting. Conclusions: Our study clearly shows that patients receiving successively the three schedules (BBR, CBR, P) have a high overall survival with manageable side effects. No significant financial relationships to disclose.

3528^ Background: Pmab is a fully human antiepidermal growth factor receptor (EGFR) monoclonal antibody approved as monotherapy for chemorefractory mCRC. ST is the most common anti-EGFR tx-related ...

e15103 Background: Bevacizumab and cetuximab regimen are approuved since 2005 in Europe for Metastatic Colorectal Cancer Patients (MCCP). Very few studies have reported data concerning the sequence (FOLFIRI BEVA and after failure CETUXIMAB- CAMPTO) in MCCP from the real world. Methods: Since 2003, in west of France, (Bretagne-Pays de Loire),a network called OMIT(Observatoire des Médicaments et Innovations Thérapeutiques) directed by Regional Health Agencies has been created. This structure gathered prospectively data from MCCP treated with targeted therapies. Since 2006, a cohort of MCCP treated successively by FOLFIRI BEVACIZUMAB (same protocol : same dose) as first line to progression or unacceptable toxicity and CETUXIMAB- CAMPTO after the first line failure was constitued (AVASTERB cohort). Criteria for initial unresectability of metastic lesions was based on investigator's evaluations during local comitee (surgeons and oncologists). In order to have a large follow up, the 35 first patients of the cohort were studied in this abstract.Age, sex, response rate to the different regimens,secondary metastatic lesion resection, time to progression to the different regimens, follow up and overall survival are the criterias studied. Results: Median age 60 years (49–83), Males : 60%, colon 71%,rectum: 17%, colorectal jonction :12%.Response rate(OR+SD)with Folfiri Bevacizumab : 45.7%. 17% of the patients underwent hepatic surgery with curative intent (all during Folfiri bevacizumab) Time to progression with Bevacizumab : 6 months. Fifty eight percent of the patients are still alive with a median follow up of 25 months (11–29)Median overall survival was not reached.The 12 months and 24 months overall survival rates are respectively 71.4% and 45.7% (date of point: 01/01/2009). Actualisation of the data will be provided during the meeting Conclusions: The results from this prospective unselected cohort of MCCP treated with the sequence FOLFIRI BEVA and after failure CETUX-CAMPTO from the real world show promising TTP, and overall survival. The study of the Kras mutation and others biomarkers could improve these results by personalization of the treatment. This part of our study is actually ongoing. No significant financial relationships to disclose.

4069 Background: Our purpose was to test the predictive value of germinal gene polymorphisms potentially linked to cetuximab, fluoropyrimidine and irinotecan pharmacodynamics on toxicity, clinical response, time to progression (TTP) and overall survival (OS). Methods: 52 patients with advanced CRC were enrolled in an ancillary pharmacogenetic study of the phase II CETUFTIRI trial (33 men, 19 women, mean age 63, range 36–84, PS 0–1). Treatment consisted in cetuximab (day 1-day 8-day 15, 250 mg/m2/week following a 400 mg/m2 loading dose) associated with irinotecan (day 1, 250 mg/m2) and UFT-folinic acid (day 1 to day 14, 250 mg/m2/day UFT, 90 mg/day folinic acid). Median number of administered cycles was 7 (range 1–8). The following gene polymorphisms were analyzed on blood genomic DNA: EGFR (CA repeats in intron 1, - 216G>T, -191C>A), EGF (61A>G), FCGR2A (131Arg>His), FCGR3A (158Phe>Val), UGT1A1 (TA repeats), TYMS (28 bp repeats including the G>C mutation on the 3R allele, 6 bp deletion in 3’ UTR), MTHFR (677C>T, 1298A>C). Results: Grade 3–4 toxicity was recorded in 59.6 % of patients. The toxicity score (sum of maximum grade for each toxicity pattern) was significantly linked to the FCGR2A genotype (median score 9, 9.5 and 13 in Arg/Arg, Arg/His and His/His patients, respectively, p = 0.035) and to the EGFR -191 genotype (median score 11 in CC patients versus 8.5 in CA patients, p = 0.040). Response rate was 49% (3 CR and 21 PR over 49 assessable patients) and was significantly higher in patients bearing the FCGR3A Val allele (62.1 % in Val/Val or Val/Phe versus 26.3 % in Phe/Phe, p = 0.020) or the TYMS 3RG allele (65.0 % versus 28.6 % in patients with no 3RG allele, p = 0.029). Gene polymorphisms did not influence TTP. A multivariate Cox analysis including gene polymorphisms and PS showed that overall survival was improved in patients bearing the FCGR3A Val allele (relative risk of death was 2.25 in Phe/Phe patients relative to Val-containing genotypes, 95% CI 1.03–4.91, p = 0.041). Conclusions: Present data suggest the importance of ADCC in cetuximab pharmacodynamics, as outlined by the role of FCGR gene polymorphisms on toxicity, responsiveness and survival. No significant financial relationships to disclose.

e15005 Background: Pmab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody approved in the US and EU (wild-type KRAS) as monotherapy for pts with mCRC. Safety data from 4 studies (Siena et al ASCO 2008; Peeters et al ASCO 2008; Cohn et al ASCO 2008; Mitchell et al WORLD GI 2008) of pmab in combination with ctx are summarized. Methods: Two studies are single-arm, phase II trials and two are randomized, phase III trials with pooled, blinded safety data that include ctx-controls. All studies were multicenter. Common pt eligibility criteria included: diagnosis of mCRC with measurable disease per modified RECIST criteria, age ≥ 18 years, and adequate hematologic, renal, hepatic, and metabolic function. All studies required pts to receive FOLFOX, FOLFIRI, or irinotecan ctx in combination with pmab. Pts received pmab 6.0 mg/kg Q2W with FOLFOX Q2W or FOLFIRI Q2W, or pmab 9.0 mg/kg Q3W with irinotecan Q3W. Results from planned interim analyses are available for 3 studies, and results from the final analysis are available for one study. Results: Among the 4-study safety data, 1213 pts received pmab + ctx; 703 pts received pmab + FOLFIRI, 455 pts received pmab + FOLFOX, and 55 pts received pmab + irinotecan. Approximately 1,200 pts were enrolled in each phase III study, and data are available from 1,003 pts who received pmab + ctx and 997 pts who received ctx alone. All pts in the phase III studies, regardless of treatment group, were included in the pooled, blinded interim analysis sets monitored by the data monitoring committee for each study. Safety results for the two phase II studies of pmab + ctx and two phase III studies of pmab ± ctx are summarized (Table). Conclusions: Phase II data are consistent with expectations, and phase III trials are ongoing. A consistent safety profile was observed across studies. [Table: see text] [Table: see text]

4055 Background: 5 randomized phase II and III trials have yet investigated the role of oxaliplatin in combination with either capecitabine (XELOX/CAPOX) or infusional 5-FU. The aim of these studies was to show non-inferiority of the oral versus the infusional combination. This meta-analysis was performed to compare the efficacy of capecitabine/oxaliplatin compared with infusional 5-fluorouracil (5- FU)/oxaliplatin regimens. Methods: This meta-analysis was based on all published summary data from reported randomized [phase II-III] trials comparing XELOX/CAPOX versus different infusional 5-FU/oxaliplatin. In total 2,575 patients (5-FU: 1,278 pts, capecitabine 1,297 pts) were included and analyzed for response rates (RR), progression free and overall survival (PFS, OS) (fixed effect & random effects models). The required estimates and standard deviations were derived from the published RR, hazard ratios (HR) and their confidence intervals (CI) or logrank p values, respectively. Results: With the exception o...

4034 Background: Pmab is a fully human anti-EGFr monoclonal antibody (MAb) with activity as a single agent in refractory mCRC. PRIME study is the first global, phase III trial investigating a fully human anti-EGFr MAb combined with FOLFOX as first-line treatment (tx) for pts with mCRC. Methods: This is a randomized, multicenter, phase III study with pt eligibility criteria which include: histologically/cytologically-confirmed adenocarcinoma of the colon or rectum with metastatic disease; no prior chemotherapy or systemic therapy for mCRC; ECOG performance status (PS) 0 to 2. No EGFr staining is required for inclusion. Pts are randomized 1:1 to receive either pmab 6.0 mg/kg Q2W + FOLFOX4 Q2W (Pmab+FOLFOX4) or FOLFOX4 Q2W alone. The primary endpoint is progression-free survival. Secondary endpoints include overall survival, objective response rate, time to progression, duration of response, and safety. PRIME study endpoints will be investigated by the pts’ KRAS mutational status in both arms as a potential ...

4028 Background: Cediranib (AZD2171) is an oral, highly potent and selective inhibitor of VEGF signaling, with activity against VEGFR-1, -2, and -3. Recent trials have shown that the combination of...

8019 Background: Survival benefits can be predicted from progression-free survival in advanced colorectal cancer (Buyse et al, JCO 2007; 25:5218), but not in advanced breast cancer (Burzykowski et al, JCO 2007; in press). We investigated whether progression-free survival (PFS) could be considered a valid surrogate for overall survival (OS) in patients with advanced non small cell lung cancer (NSCLC). Methods: Individual patient data were collected from all trials comparing docetaxel to vinca alkaloids for the first-line treatment of patients with NSCLC (Douillard et al, J Thoracic Oncol 2007;2:939). Surrogacy of PFS for OS was assessed through the association between these endpoints and between the treatment effects on these endpoints. Treatment effects were estimated through hazard ratios in the 322 participating centers. Centers with less than 3 patients per treatment arm were grouped. Squared correlation coefficients were estimated along with their 95% confidence interval (CI). The surrogate threshold ...

4088 Background: Irinotecan combined with 5FU/LV improves the outcome of patients (pts) with advanced colorectal cancer. R98 trial tests the hypothesis that this combination is superior to 5FU/LV a...

7553 Background: Adjuvant cisplatin-based chemotherapy (CT) has been shown to increase survival in NSCLC, but uncertainty exists concerning its efficacy and toxicity in elderly patients (≥ 70). Methods: We performed a pooled analysis using individual patient data from 4,584 patients in the LACE database with resected stage IA-III NSCLC enrolled in 5 randomized trials, comparing postoperative CT to no CT (ALPI, ANITA, BLT, IALT and JBR10). Patient and treatment characteristics, CT toxicity and delivery, overall survival, disease-free survival (DFS) and cause-specific mortality were compared among 3 age groups: 3,269 (71%) young (300), gender, stage, performance status, type of surgery and histology were used with a test for trend to study the effect of CT on survival according to age. Results: Baseline characteristics differed among the age groups, but this was due mainly to the different trial populations and designs. No difference in severe toxicity rate was observed among the age groups. Elderly patients received significantly smaller total doses of cisplatin than the other patients (Chi2-test: p No significant financial relationships to disclose.

4087 Background: A phase II study (ASCO 2004) established that the combination of UFT (tegafur-uracil) with LV and irinotecan (TEGAFIRI) could be safely administered to pts with unresectable mCRC, with an objective response rate (ORR) of 34% and a median time to progression (TTP) of 5.7 months. We initiated CETUFTIRI, a phase II study, to evaluate the efficacy and tolerability of cetuximab added to TEGAFIRI in chemonaïve pts with unresectable mCRC. Methods: Patients in this single-stage study were aged =18 years, with histologically or cytologically confirmed, bidimensionally measurable mCRC, ECOG performance status 0 or 1, and adequate bone marrow, renal, and hepatic function. EGFR expression was not an inclusion criterion. Treatment consisted of UFT 250 mg/m2/day d1–14, LV 90 mg/day d1–14, and irinotecan 250 mg/m2 d1 every 3 weeks, plus cetuximab 400 mg/m2 week 1 then 250 mg/m2 weekly thereafter. The primary endpoint was ORR and the planned sample size was 61 pts. The study is now closed to accrual. Results: To date, 48 patients are evaluable for safety and 31 are evaluable for efficacy. Patient characteristics (n=48): median age 65 years (range 45–84 years); ECOG PS 0/1: 73/27%; male 65%; tumor sites: colon 69%; rectum 17%; junction 14%; liver metastasis 83%; lung metastasis 46%; other 27%. Adverse events per patient (n=48) after a total of 230 cycles were: grade G3 mucositis 10%; G3/4 neutropenia 10%; G3 nausea/vomiting 8%; G3 asthenia 6%; febrile neutropenia 6%; G3 hypokalemia 6%; G3/4 anemia 4%; G3 diarrhea 2%; acne-like rash G1/2 50% (G3 4%); infusion- related reaction to cetuximab 6%. Two of 31 evaluable pts had a complete response and 11 had a partial response, for an ORR of 42%; 5 pts had stable disease (16%) and 11 pts had progressive disease (35.5%). An independent radiologist review is planned for all 61 pts included up to December 2006. Conclusions: The CETUFTIRI combination seems to have an acceptable toxicity profile with an attractive objective response rate in the first-line treatment of pts with mCRC. No significant financial relationships to disclose.

4029 Background: X has comparable efficacy, safety and convenience benefits over 5-FU/LV (Mayo clinic) in adjuvant colon cancer and first-line MCRC. A recent phase III trial in first line MCRC showed that XELOX is well tolerated and non inferior to FOLFOX-4 for progression-free survival (PFS) [Cassidy ESMO 2006]. Methods: We initiated a phase III trial to demonstrate non inferiority in terms of best response rates (RR, RECIST) of XELOX versus FOLFOX-6 as first-line therapy in patients (pts) with MCRC. Between 16 May 03 and 31 Aug 04, 306 patients (intention to treat), were randomized to receive either XELOX (n=156: × 1,000mg/m2 bid d1–14, O 130mg/m2 d1, q3w) or FOLFOX-6 (n=150: O 100mg/m2 d1 LV 400mg/m2 2h infusion then 5-FU 400mg/m2 i.v. bolus then 2,400–3,000mg/m2 46h infusion, q2w) for 6 months. Efficacy results are presented in the per protocol population (PP) (n=284:144 pts XELOX; 140 pts FOLFOX-6). Results: Baseline characteristics were well balanced. Pts received a median of 8 and 11 cycles of XELOX (range 0–8) and FOLFOX-6 (range 0–12), respectively. Dose intensity (median) for oxaliplatin was 99.6% and 95.4% with XELOX and FOLFOX-6, respectively. Best RR (independent review, PP) was 42% and 46% with XELOX and FOLFOX-6, respectively. Difference between groups for RR was 4.7%; upper limit of 95% unilateral CI (14.4%) was below non-inferiority margin of 15%. RR by investigators (PP) was 46% for each arm. With a median follow up of 16.5 months (range 0.4–38.3), median PFS and overall survival (PP) were 9.3/19.9 vs. 9.7/18.4 months with XELOX and FOLFOX-6, respectively. In the safety population (n=304), XELOX pts had more grade 3/4 hand-foot syndrome (3 vs. 0%, p=0.21), thrombocytopenia (12 vs. 5% p=0.052), and diarrhea (12% vs. 7% p=0.1), but less grade 3/4 febrile neutropenia (0 vs. 6% p=0.001), neuropathy (8 vs. 19% p=0.003), than those on FOLFOX-6. Treatment discontinuation for toxicity was 19% and 23% in XELOX and FOLFOX-6 arms, respectively. Conclusions: The primary endpoint has been met: XELOX is non inferior to FOLFOX-6, with a good safety profile in first-line MCRC. No significant financial relationships to disclose.

4083 Background: A recent phase III trial in first-line MCRC showed that XELOX is well tolerated and non inferior to FOLFOX-4 in terms of progression-free survival (PFS) [Cassidy ESMO 2006]. We conducted a phase III trial of XELOX vs. FOLFOX-6 as first-line treatment for MCRC. Methods: 306 patients were randomized to receive either XELOX (n=156: capecitabine 1,000mg/m2 bid d1–14, oxaliplatin 130mg/m2 d1, q3w) or FOLFOX-6 (n=150: oxaliplatin 100mg/m2 d1 LV 400mg/m2 2h infusion then 5-FU 400mg/m2 i.v. bolus then 2,400- 3,000mg/m2 46h infusion, q2w) for 6 months. Primary objective: demonstrate non-inferiority of XELOX (best response rate, RECIST). A cost minimization has been conducted from the French hospital perspective. The hospitalizations for chemotherapy (drug administration) were compiled and the direct hospital costs estimated using official tariffs of the national ‘PMSI’ database, directly derived from the Diagnosis Related Group (DRG). Results: The ITT population comprises 306 patients (156 on XELOX, 150 on FOLFOX-6). Baseline characteristics were well balanced. Patients received an average of 6.1±2.4 and 9.2±3.2 cycles of XELOX and FOLFOX-6, respectively. The number of hospitalizations was 6.5±2.6 and 9.5±4.1 for XELOX and FOLFOX-6, respectively. The costs of hospitalization for chemotherapy are available for 282 patients (142 in the XELOX arm and 140 in the FOLFOX-6 arm). The average cost of chemotherapy per cycle per patient was 608±446€ in the XELOX arm and 1,043±787€ in the FOLFOX-6 arm (p No significant financial relationships to disclose.

4071 Background: Irinotecan containing first line therapy has been shown to improve efficacy in first line therapy. Pooled analyses demonstrated that elderly patients benefit in a similar way as younger patients if 5-FU or 5-FU/oxaliplatin is administered as palliative or adjuvant treatment within clinical trials (Sargent, NEJM 2001, Folprecht, Ann Oncol 2004, Goldberg JCO 2006). Methods: We present an updated metaanalysis using source data of randomized trials (Saltz 2000, Douillard 2000, Köhne 2005 [EORTC 40986] and Seymour 2005 [FOCUS]) and compared the efficacy and toxicity in older (=70 years) and younger (= 3 toxicity in the general population, but there were no significant differences regarding toxicity between older and younger patients ( table 1 ). Conclusion: Patients over 70 yrs who are selected for inclusion in phase III trials derive similar benefits from irinotecan-containing chemotherapy, and with similar risks of toxicity, compared with younger patients. [Table: see text] [Table: see text]

4018 Background: Disease-free survival (DFS) is the primary endpoint of most trials testing adjuvant treatments. However many other endpoints are used. There is much confusion about these endpoints since different definitions were used among trials, or no definitions were provided at all. Moreover there is no consensus on either the definition of each endpoint or on the most relevant among these endpoints. This creates difficulties when comparing the results of various trials. Methods: Adjuvant trials in colon cancer were used as a model. A systematic review was performed on published adjuvant studies in colon cancer from 1997–2006, and the definitions of endpoints other than overall survival (OS) were recorded. A panel of medical oncologists, surgical oncologists, and a statistician, all with expertise in randomised trials in colorectal cancer, aimed to reach consensus on the definition of the various endpoints as well as to select the most relevant among these. Results: A total of 52 studies were identified. In addition to overall survival 8 other endpoints were used, and both the definition of these endpoints as well as the starting point differed considerably among these studies. No definition was provided for the endpoint in 19 (37%) studies and for the starting point in 30 (58%) studies. The panel reached consensus on the definition of each endpoint ( table ), and agreed that DFS, defined as the time from randomisation to any event irrespective of cause was considered to be the most relevant endpoint for adjuvant studies. The date of randomisation was considered to be the most appropriate starting point. Conclusions: The proposed guideline will help in the design of future adjuvant studies in colon cancer, and will achieve the uniformity required to facilitate cross-study comparisons. It may serve as a model for adjuvant studies in other solid tumors. [Table: see text] No significant financial relationships to disclose.

4099 Background: A recent phase III trial in first-line MCRC showed that XELOX is non-inferior to infusional 5-FU + oxaliplatin (FOLFOX-4) for progression-free survival (PFS) [Cassidy ESMO 2006]. Here we present safety and QoL findings from a study of XELOX vs. FOLFOX-6 in first-line MCRC. Methods: Between 16 May 03 and 31 Aug 04, 306 patients (pts) were randomized to receive either XELOX (156 pts: × 1,000mg/m2 bid d1–14, O 130mg/m2 d1, q3w) or FOLFOX-6 (150 pts: O 100mg/m2 d1 LV 400mg/m2 2h infusion then 5-FU 400mg/m2 i.v. bolus then 2,400–3,000mg/m2 46h infusion, q2w) for 6 months. Primary objective: demonstrate non inferiority of XELOX in terms of best response rate (RECIST). Secondary objectives: evaluate QoL and pt satisfaction with care by EORTC QLQ-C30 and FACIT (chemotherapy convenience and satisfaction) questionnaires. Pts completed questionnaires at baseline, before cycles 3/4, 6/8 and at final visit in XELOX/FOLFOX-6 arms, respectively. Results: 245 pts (QLQ-C30) and 225 pts (satisfaction) were evaluable for QoL. The compliance rate was >70%. At baseline, QoL scores were not significantly different. QLQ-C30 functional and symptomatic scores were stable in both arms. According to FACIT, there was no difference between arms, although XELOX-treated pts wasted less hours of their free time than those on FOLFOX-6: 10±23 vs. 37±68 hours, respectively (p=0.007). XELOX was a more ‘comfortable’ treatment (p No significant financial relationships to disclose.

3578 Background: Irinotecan has been shown to improve response rate and progression free survival in three randomized studies. In a recent metaanalysis showed that elderly patients have a similar benefit from 5-FU containing palliative treatment as younger patients (Folprecht 2004). Methods: We performed a metaanalysis of three randomized trials investigating 5-FU/FA/irinotecan vs. 5-FU/FA (Saltz 2000, Douillard 2000, Köhne 2005 [EORTC 40986]), and one phase II trial with 5-FU/irinotecan (Sastre 2005) to explore the efficacy and toxicity in elderly (≥70 years) and non-elderly (< 70 years) patients. Only data from randomized trials were used to compare the treatment arms 5-FU/FA plus irinotecan (IFL, FOLFIRI or Irinotecan/AIO) vs. 5-FU/FA (Mayo clinic regimen, LV5FU2 or AIO). Results: In total, 303 patients ≥70 y. and 1181 patients < 70 y were analyzed. Overall response rate was 39.5% in elderly and 33.1% in non-elderly patients (p=.055). Progression free survival was 6.7 (5.6–7.8) and 5.7 (5.2–6.1) months in elderly and younger patients (p=.12), respectively, overall survival 15.9 (13.6–18.3) vs. 15.4 (14.3–16.5) months (p=.9). Neutropenia gr. 3/4 and stomatitis gr. 3/4 was found to be more frequent in elderly patients. No differences were found in the other toxicities. Conclusion: The analysis confirms that neutropenia and stomatitis is moderately increased in elderly patients. However elderly patients benefit from treatment with irinotecan/5-FU in a similar way as younger patients do, and (fit) elderly should be offered the irinotecan-containing therapy in the same way as younger patients. [Table: see text] No significant financial relationships to disclose.

13518 Background: In the X-ACT adjuvant trial, X showed consistent benefits over bolus 5-FU/LV, with at least equivalent disease-free survival (DFS) and an improved safety profile [Twelves et al. 2005]. In addition, X demonstrated superior relapse-free survival (65.5% vs. 61.9% at 3 years follow-up; p=0.0407) and improved covariate-adjusted overall survival (p=0.0208). We used the results from X-ACT to assess the cost-effectiveness of X from the Italian hospital and societal perspective. Methods: Trial-based data were collected on treatment period medical resource use. Unit costs for drug administration, hospitalizations, emergency room visits, and concomitant medications were considered using published sources in Italy. Cost for physician consultation visits, pt time and travel were also considered in the societal perspective. A health-state transition model was used to estimate incremental cost impact and the effectiveness in terms of gains in quality-adjusted life months (QALMs). Costs and effectiveness were discounted at 3.5%. Results: Mean duration of treatment was similar with X and 5-FU/LV; pts received 92% and 93% of planned treatments, respectively. Administration of X required fewer clinic visits per pt (7.4 vs. 28.0 with 5-FU/LV). Acquisition costs of X were higher than 5-FU/LV, approximately 2533 vs. 231€, but this difference was more than fully offset by the difference in administration cost of 5-FU/LV (4338 vs. 152€ for X). Total hospital days for treatment-related adverse events (AEs) and medication costs for treating AEs were higher for 5-FU/LV than X. The cost of emergency room visits for treating AEs and physician consultation did not differ. Compared with 5-FU/LV, X is projected to increase QALMs by 6.5 months, with overall treatment period cost savings of 2234€ for the hospital. From a societal perspective, the cost savings increase to 3976€. These findings show that X is a dominant (cost-saving and more effective) treatment in this setting. Conclusions: X as adjuvant treatment for pts with colon cancer is clinically effective with an improved safety profile vs. 5-FU/LV and is also a dominant choice from an economic perspective. [Table: see text]

3508 Background: PTK/ZK is a novel, oral, small molecule, antiangiogenic compound that inhibits tyrosine kinase signaling of all known vascular endothelial growth factor (VEGF) receptors. Methods: 855 pts were randomized to FOLFOX4 plus PTK/ZK (1250 mg, qd), or placebo. Eligibility included histologically or cytologically documented mCRC, pretreatment for metastatic disease with irinotecan/fluoropyrimidine-based chemotherapy, measurable disease by RECIST, PS of 0–2 and adequate organ and bone marrow function. The primary endpoint is overall survival (OS). Secondary endpoints included OS and PFS in high LDH pts (stratifiedbybaseline serum LDH levels > 1.5 × ULN). Results: OS was 12.1 mo in the PTK/ZK arm and 11.8 mo in the placebo arm (HR: 0.94; p=0.511). A pre-planned triangular test suggested a low probability of demonstrating an improvement in OS at the final analysis (4Q 2006). The response rates (CR+PR) were 18.5% in the PTK/ZK arm, 17.5% in the placebo arm. PFS was significantly longer in the PTK/ZK arm (5.5 mo vs. 4.1 mo; HR: 0.83; p=0.026). LDH, usually a poor prognostic factor in mCRC, is predictive of the outcome in the PTK/ZK arm. Pts with high LDH showed a strong improvement in PFS when treated with PTK/ZK (5.6 mo vs. 3.8 mo; HR: 0.63; p [Table: see text]

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]

7034 Background: Taxanes and vinca alkaloids are commonly used agents, in first-line therapy of advanced NSCLC. As some data in comparative studies have suggested possible differences in survival and safety, we performed a meta-analysis in order to assess the potential benefit of docetaxel-based regimens in comparison with vinca alkaloid-based regimens, in terms of overall survival (OS) and toxicity. Methods: MEDLINE, CANCERLIT and Cochrane Library searches were supplemented by information from clinical study reports and by manual searching of relevant meeting proceedings. Only randomized trials comparing docetaxel-based chemotherapy to vinorelbine- or vindesine-based chemotherapy were included. Outcomes recorded were OS and neutropenia. Fixed-effects and random-effects models were used to estimate the pooled hazard ratio (HR) of OS and the odds ratio (OR) of neutropenia. A HR or OR less than 1 indicates that docetaxel is superior to vinca alkaloids. Heterogeneity was assessed using the Cochran Q-test. Results: The seven selected trials (six using vinorelbine as vinca alkaloid) yielded a total of 2,867 patients (docetaxel regimens: 1,638; vinca alkaloid regimens: 1,229). Docetaxel was combined with a platinum compound in three trials, with gemcitabine in two trials and used as monotherapy in two trials. The vinca alkaloid was combined with a platinum compound in six trials, and used alone (vinorelbine) in one. The pooled estimate of the OS shows a significant improvement in favor of docetaxel (HR=0.89, 95%CI [0.82;0.96], p=0.03), this benefit persisting after exclusion of the vindesine study (HR=0.90 [0.83;0.98]) and also after excluding monotherapy regimens (HR=0.89 [0.82;0.97]. While neutropenia was common, it was significantly less frequent with docetaxel (OR=0.60 [0.39;0.92], p=0.019), as was febrile neutropenia (OR=0.60 [0.39;0.96], p=0.034). Conclusions: The results of this meta-analysis support the superior efficacy (OS) and safety (neutropenia and febrile neutropenia) of docetaxel in first-line therapy of advanced NSCLC as compared with vindesine or vinorelbine. Detailed results, as well as subgroup analyses, will be presented at the meeting. [Table: see text]

12013 Background: This phase II randomized bioequivalence cross-over study compared the tolerance and PK profiles of oral UFT (tegafur-uracil) given as 3 daily intakes (tid, usual schedule) to that obtained with 2 daily intakes (bid). Methods: Twenty-one metastatic colorectal cancer patients were enrolled (16 men, 5 women ; mean age 64, extremes 42–79 ; ECOG PS ≤ 1). Tegafur-uracil (300 mg/m2/d) and leucovorin (90 mg/d) were given for 2 consecutive four-week cycles separated by one rest week. Patients were randomized for receiving 1st cycle either tid (arm A, 12 patients) or bid (arm B, 9 patients). For each schedule, PK was evaluated at steady state, over 24 h. Plasma concentrations of tegafur, uracil and fluorouracil (FU) were analyzed by HPLC. Results: Analysis of tolerance (digestive toxicity mainly, OMS grade) showed a tendency (p = 0.08) for a greater toxicity with the bid schedule (29% grade 2, 14% grade 3) relative to tid (24% grade 2 only). Although daily doses were similar, FU and uracil AUC0–24h were respectively 1.8 and 2.0-fold higher for bid as compared to tid (95% CI were 1.5–2.1 and 1.6–2.6, respectively, p < 0.0001). For tegafur, the 1.2-fold difference was of borderline significance (p = 0.057). The greater the FU AUC0–24h, the higher the toxicity intensity (p = 0.044). Analysis of systemic exposure with respect to daily time revealed that FU (p < 0.01) and uracil (p < 0.03) AUC corresponding to the morning intake were significantly higher than those corresponding to the afternoon or evening intakes, with AUC ratio as high as 1.6 for FU and 2.9 for uracil. Such a circadian influence was not observed for tegafur. Conclusions: To reach bioequivalence, bid tegafur-uracil administration will require lower doses than those given tid. The circadian variability observed for FU and uracil PK concords with that previously reported for dihydropyrimidine deshydrogenase activity. No significant financial relationships to disclose.

7016 Background: Since local failure remains frequent after RT in these patients (pts), a randomized trial was designed to assess the efficacy of concurrent daily RT-Cb given after induction chemotherapy (ICT) on local control. Method: Unresectable stage III NSCLC pts (any weight loss, WHO PS 0–2, ± supraclavicular lymph node or superior vena cava syndrom) were eligible. ICT (Vr 30 mg/m2, week (w) 1, 3, 5, and 15 mg/m2, w 2, 4, 6; P 120 mg/m2 w 1 and 5) was modified (Vr 30 mg/m2 w 1 to 9; P 100 mg/m2 w 1, 5 and 9) after 1st interim analysis (190 pts accrued) due to high incidence of metastases. CR, PR, SD pts after ICT were given RT (66 Gy, 33 fractions) with (arm B) or without (arm A) daily Cb (15 mg/m2) according to randomization performed at entry (stratification on gender, PS, histology and center). Evaluation using CT scan was performed 1 month (m) after RT, every 3 m for 3 yrs, every 6 m thereafter. To demonstrate a 10% improvement on the 1-yr local control rate, 585 pts were needed (2 interim and 1...

3502 Background: LV5FU2+CPT-11 has shown more activity than LV5FU2 alone in first line metastatic colorectal cancer. This adjuvant trial evaluated the addition of CPT-11 to LV5FU2 in terms of Event-Free Survival (EFS) and safety in colorectal cancer patients (pts) at a high risk of relapse. Methods: Colon cancer pts with postoperative N2 or N1 detected by occlusion/perforation were randomized to either: A: LV5FU2 (leucovorin 200mg/m2 as a 2-h infusion, 5-FU 400mg/m2 bolus and 600mg/m2 22-h continuous infusion, d1–2) or B: LV5FU2+CPT-11 (irinotecan 180mg/m2 90-min infusion d1+LV5FU2) fortnightly for 12 cycles without any support of growth factors. Pts were stratified by center, type of detection, delay from surgery to chemotherapy (≤28d; >28d) and age (

7266 Background: VFL (Javlor) is a novel semi-synthetic vinca-alkaloid that has shown higher in vivo antitumour activity than vinorelbine in several human tumour models. In NSCLC, non-platinum doub...

3596 Background: The oral fluoropyrimidine X has superior efficacy and improved safety compared with bolus 5-FU/LV in MCRC. Twice-daily oral X mimics 5-FU infusion and is replacing 5-FU in combinat...

2536 Background: Vγ9Vδ2 (γδ) T lymphocytes, a critical peripheral blood lymphocyte (PBL) subset, are directly cytotoxic against several tumor types, including renal carcinoma cells (RCC). (γδ) lymphocytes can be selectively expanded in vivo with BrHPP (Phosphostim) and IL-2. We conducted a phase I trial, to define the dose limiting toxicities (DLT), characterize PK and PD, and recommend a dose for phase II studies. Methods: Patients (pts), with advanced solid tumors and no organ dysfunction and PS of 0–1 were included. A single, one hour intravenous infusion of BrHPP was administered alone at cycle 1, combined with low dose of SC IL-2 (1 MIU/M2 d1 to d7) in the subsequent cycles (day 1 every 3 weeks). BrHPP dosage was escalated in cohorts of 3 pts extended to 6 if 1/3 patients on a dose level had a DLT. Results: 18 pts (10 mRCC, 1 colon, 2 breast, 1 ovarian, 1 gastric, 3 oesophageal cancer) have been enrolled to date at 4 dose levels: 4 pts 200 mg/m2, 3 pts 600 mg/m2, 6 pts 1200 mg/m2, 5 pts 1800 mg/m2. A...

3549 Background:The optimal adjuvant treatment of stages II-III rectal cancers is still debatable. When administered, postoperative chemotherapy is usually a 5FU-leucovorin (5FU/LV) regimen. CPT-11...

3692 Background: Surgical resection of LM is the only treatment able to offer long term survival (30–35% at 5 years); however most LM are initially unresectable. Methods: The aim of this retrospect...

3545 Background: UFT/LV has demonstrated comparable efficacy to 5-FU/LV iv regimens with clinical safety advantages [Douillard, Carmichael JCO 2002]. 5-FU based regimens containing irinotecan or oxaliplatin are the standard of care for pts with first line MCRC [Douillard, lancet 2000, de Gramont JCO 2000]. UFT/LV is an orally available treatment, and is a potentially valuable alternative to infusional regimens. Based on these results, we conducted two phase II trials of UFT/LV in combination with oxaliplatin and irinotecan. Methods: Eligibility criteria were similar in both studies. Pts with measurable non-resectable MCRC were included to evaluate efficacy (Objective Responses Rate) and safety of UFT/LV when combined with oxaliplatin (Tegafox trial) and irinotecan (Tegafiri trial) as first line treatment of MCRC. UFT was administered at 300 mg/m2/day d1–14, LV 90 mg/day d1–14 with oxaliplatin 130 mg/m2/day d1 every 3 wks and at 250 mg/m2/day d1–14, LV 90 mg/day d1–14 with irinotecan 250 mg/m2 d1 every 3 w...

3576 Background: With only one 5FU bolus injection and an increased dose of 5FU by continuous infusion, the simplified LV5FU2 regimen is considered as effective as but less toxic and more convenient than the original LV5FU2 de Gramont regimen [Tournigand ASCO 1998 #1052]. LV5FU2-CPT11 and FOLFIRI are safe and active in the front-line treatment of metastatic colorectal cancer [Douillard Lancet 2000 –V303 trial, Tournigand JCO 2004 –V308 trial]. In both regimens, CPT11 is given at a dose of 180 mg/m2 combined with the LV5FU2 regimen for LV5FU2-CPT11 or with the simplified LV5FU2 regimen for FOLFIRI. Methods: We performed a comparison based on the individual data from the V303 and V308 trials to assess the safety profile and efficacy of LV5FU2-CPT11 and FOLFIRI. Main severe adverse events (NCI grade 3–4) possibly and probably related to treatment as well as the objective response rate (ORR) and progression-free survival (PFS) were compared by treatment group. Results: 145 pts received the LV5FU2-CPT11 combin...