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3537 Background: Bevacizumab (BV) prolongs overall survival and progression-free survival (PFS) when added to standard chemotherapy (CT) in patients with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of patients with mCRC receiving BV plus first-line CT. Safety and efficacy information in unselected patients with mCRC are collected. Chemotherapy regimen choice is at the physician’s discretion. Methods: 1968 patients receiving BV plus first-line CT were enrolled at 248 sites in 49 states between Feb 2004 and Jun 2005. Patients are followed for up to 3 years, with data reporting every 3 months (mo) including disease status as assessed by investigator using his/her method of choice. Patients were grouped twice by CT. Cox regression models, adjusted and unadjusted for treatment assignment, were used to identify baseline characteristics (BC) and differential chemotherapy effects on PFS. Results: Cohort demographics were consistent with the NCI Surveillance, Epidemiology, and End Results (SEER) database for mCRC. Median study follow-up was 10 months by Nov 4, 2005. CT regimens included FOLFOX (55.8%), FOLFIRI (14.1%), and IFL (9.7%). Based on observed progression events (n=800) or deaths (n=123), projected median PFS is 11.3 mo (95% CI: 10.4–11.7). Median PFS was comparable in patients treated with CT regimen based on irinotecan (11.3 mo), oxaliplatin (11.4 mo), or neither (10.2 mo) (CT Grouping 1); or 5FU infusion (11.5 mo), 5-FU bolus (9.7 mo), or capecitabine (11.6 mo) (CT Grouping 2). Significant BC in adjusted and unadjusted models are ECOG performance status (PS), primary disease site, and albumin, with no significant difference among CT regimens. Conclusions: This large, community-based registry included a patient population with demographics consistent with the SEER database for mCRC. Preliminary median PFS of 11.3 mo compares favorably to that reported in the pivotal trial. Median PFS appears to be comparable for all CTs when combined with BV. Higher baseline albumin, PS of 0, and primary disease site of rectum were associated with improved outcome. [Table: see text]

3536 Background: Bevacizumab (BV) prolongs overall survival and progression-free survival when added to standard chemotherapy for patients with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of patients with mCRC receiving BV plus first-line chemotherapy. Safety and efficacy information in unselected patients with mCRC are collected. Chemotherapy regimen choice is at the physician’s discretion. Methods: To facilitate and evaluate enrollment of a typical community-based mCRC population, eligibility criteria were minimized. Cohort demographics were consistent with the NCI Surveillance, Epidemiology, and End Results (SEER) database for mCRC. Patients are followed for up to 3 years, and safety data including targeted BV-associated serious adverse events (SAEs) are updated every 3 months (mo). Results are based on descriptive analyses and are not adjusted for propensity of treatment, baseline characteristics, and treatment effects. Results: 1968 patients were enrolled between Feb 2004 and Jun 2005. Median study follow-up was 10 mo by Nov 4, 2005. SAEs were reported in 12.0% of patients including gastrointestinal perforation (GIP) (1.7%), postoperative bleeding/wound healing complications (1.2%), arterial thromboembolic events (ATE) (2.1%), and grade 3–4 bleeding (1.9%). 3.2% of patients discontinued BV due to a BV-related toxicity, most commonly bleeding. For patients with the respective event(s), median time to first event was 2.1 mo for GIP, 3.5 mo for ATE and 4.0 mo for grade 3–4 bleeding. 8.9% of patients with no history of hypertension (HTN) developed HTN requiring medication and 6.2% of patients who had HTN requiring medication at baseline experienced worsening of their HTN while on study treatment. Conclusions: In this unselected population of patients with mCRC, the safety profile of BV plus various chemotherapy regimens appears consistent with that observed in the pivotal BV trial. Overall discontinuation of BV due to a BV-related toxicity was uncommon. In this large community-based observational registry, no new BV associated safety issues have been identified. [Table: see text]

3535 Background: Bevacizumab (BV) prolongs overall survival and progression-free survival when added to standard chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of pts with mCRC receiving BV plus first-line chemotherapy (CT). Incidence rate, temporal pattern, and potential risk factors associated with gastrointestinal perforation (GIP) were explored. Methods: Baseline patient characteristics (BC), including prospectively identified potential risk factors for GIP, were collected at study entry. Safety data were collected every 3 months (mo). Logistic regression models, adjusted and unadjusted for treatment assignment, were used to identify BC potentially associated with GIP. Results: 1968 pts were enrolled between Feb 2004 and Jun 2005. Median study follow-up was 10 mo as of Nov 4, 2005. GIPs were observed in 34 pts (1.7%). For pts with GIP, median time to first event was 2.1 mo; the majority of events were non-fatal and occurred within the first 3 mo after starting BV. BC including GI medical history (chronic aspirin or NSAID use, peptic ulcer disease, diverticulosis) were similar in pts with or without GIP and with earlier or later GIP onset (≤ or >3 mo from start of BV). Although adjusted models did not show any significant BC, GIP rates were numerically higher in pts with primary tumor intact (2.6%) vs. resected (1.6%). Furthermore, univariate analyses revealed a significant difference between intact (2.3%) and resected (0.8%) primary tumor for earlier GIP (≤3 mo from start of BV). The majority of pts with GIP had at least one of the following: acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, tumor at GIP site, abdominal carcinomatosis, prior abdominal or pelvic radiation therapy. Conclusions: Preliminary analyses indicate the incidence of GIP in this large, community-based observational registry is similar to that previously reported in phase III mCRC trials with BV. No associations between specific BCs and an increased risk of GIP were identified. Patients with primary tumor intact were more likely to incur a GIP within the first 3 mo of starting BV and CT. [Table: see text]

3516 Background: A previous report noted that patients (pts) in the phase III study of IFL ± BV who received BV had significantly longer PFS and OS regardless of whether or not they responded according to RECIST criteria (Mass et al, ASCO 2005). It is unclear if this phenomenon is specific to the addition of a biologic to chemotherapy (CT) or a more general benefit from improved therapy since it has been suggested that stable as well as responding disease is beneficial for pts. We repeated the analysis of Mass et al on pts enrolled in N9741, a study which established the superiority of FOLFOX over IFL and contained no biologic compound. Methods: For this retrospective analysis, pts were defined as ‘responders‘ or ‘nonresponders‘ according to whether criteria for complete or partial response (by RECIST -AVF2107g or WHO criteria -N9741) were either achieved (responders) or not achieved (nonresponders). PFS and OS were estimated from Kaplan-Meier curves; hazard ratios (HR) for progression and death in each subgroup were estimated by Cox regression. Results: In both trials, response was associated with superior outcome. However, statistically significant improvements in PFS and OS were observed in both responders and non-responders treated with either IFL + BV or FOLFOX versus IFL, and the magnitude of improvement was similar regardless of response ( Table ). Conclusions: Analysis of two large recent mCRC phase III trials clearly demonstrate that pts who do not achieve a response according to traditional criteria still have significant benefit from the superior regimen, with a similar magnitude of benefit for responders and non-responders, regardless if the regimen called for CT alone or included the antiangiogenic biologic BV. These data support the conclusion that PFS and the percentage of pts experiencing tumor control may more accurately reflect pt benefit than does response rate in phase III trials in mCRC. [Table: see text] [Table: see text]

4555 Background: Combination chemotherapy is widely accepted for patients with advanced gastric cancer, but uncertainty remains regarding the choice of the regimen. Methods: Our objectives were to assess the effect of: 1) 5-FU/cisplatin combinations with versus without anthracyclines; 2) 5-FU/anthracycline combinations with versus without cisplatin; 3) Irinotecan versus non-irinotecan containing combination chemotherapies; 4) Docetaxel versus non-docetaxel containing combinations; on overall survival and toxicity. Search strategy: We searched: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, proceedings from DDW, ECCO, ESMO, ASCO until october 2006. Selection criteria: Randomised controlled trials on different combination chemotherapies as above in advanced gastric cancer. Results: 13 trials including in total 2,184 patients (pts) are included in this meta-analysis. Comparison 1) including 501 pts (HR 0.77; 95% CI 0.62–0.95); and 2) including 1,147 pts (HR 0.83; 95%CI 0.76–0.91) both demonstrate a significant survival benefit for three-drug regimens including 5-FU, anthracyclines and cisplatin. Among these, the rate of treatment-related deaths was higher when 5-FU was administered as bolus compared to infusional 5-FU (exact Mantel-Haenszel OR 2.33, p=0.285). Comparison 3) including 536 pts results in a HR of 0.88; 95% CI 0.73- 1.06. The rate of treatment related deaths was 0.7% versus 2.6% in the irinotecan versus non-irinotecan-containing arms (exact Mantel-Haenszel OR 0.275, p=0.166). Comparison 4) 4 relevant trials were identified. A meta-analysis will be performed as soon as the final results of at least 3 trials are available. Conclusions: Three-drug regimens containing 5-FU, anthracyclines and cisplatin achieve superior survival results compared to cisplatin/5-FU or antracycline/5-FU combinations. Among these, ECF (epirubicin, cisplatin and 5-FU) is tolerated best. Combinations including irinotecan demonstrate a non-significant trend towards better survival in this meta-analysis, but have never been compared against three-drug regimens containing 5-FU/cisplatin and an anthracycline. Supported by: KKS Halle, grant number [BMBF/FKZ 01GH01GH0105]. No significant financial relationships to disclose.

4136 Introduction: BV prolongs overall survival (OS) and progression-free survival (PFS) when added to 1st- or 2nd -line chemotherapy (CT) in mCRC. Though serious toxicities specific to BV are uncommon, a retrospective pooled analysis of 5 randomized trials showed an association of arterial thromboembolic events (ATEs) with BV use (3.8% vs 1.7% with CT alone), with age ≥65 and prior history (Hx) of ATE identified as associated risk factors (Skillings, JCO 2005). The BRiTE mCRC registry evaluated BV-associated serious adverse events (SAEs), including ATEs presenting as SAEs (sATE), in a general practice setting. Methods: Pts and methods have been described (Hedrick ASCO 2006). Hx of sATE, timing of prior sATE relative to starting BV, and anti-platelet agent (anti-plt) use were summarized. Definition of sATE included myocardial infarction (MI), cerebral vascular accident (CVA), transient ischemic attack (TIA), and peripheral arterial disease. Incidence rate of sATE was expressed as events per pt-yr of follow-up. Fisher’s exact test and multiple logistic regression was used to assess the univariate and multivariate associations. Results: Median follow- up was 17.5 mo. Of 1953 evaluable pts, 45.9% (n=896) were ≥65, 18.0% (n=352) had Hx of sATE, and 11.2% (n=219) received anti-plt. A total of 38 sATE [CVA (n=14), MI (n=11), sudden cardiac death (n=1), TIA (n=7), and other (n=5)] were reported in 34 (1.7%) pts. Median time to sATE was 3.6 mo. The calculated sATE rate was 2.2/100 pt-yr overall and 4.7/100 pt-yr in pts with prior sATE. Table 1 summarizes the results of univariate and multivariate analyses. Conclusions: In this series of BV-treated pts, the incidence of sATE associated with BV use was comparable with the rate of analogous events reported in previous controlled trials of BV in mCRC. In this series, prior history of sATE and ECOG PS were found to be associated with sATE risk in multivariate analyses. [Table: see text] [Table: see text]

4080 Background: Waterfall plots have been used to capture the anti-tumor efficacy of both biologic agents (Ratain JCO 2006), which mainly exhibit a cytostatic effect, but also of chemotherapeutic agents. We are not aware of an application to therapeutic studies in CRC. We conducted waterfall plot analyses on the data of N9741 which compared IFL, FOLFOX4, and IROX as first-line therapy in ACRC (Goldberg JCO 2004). Methods: 634 (IFL 215, FOLFOX 215, IROX 204) of the 795 pts presented in the published analysis had measurable disease, and are included. The percentage change in tumor measurements from baseline to 12 wks was calculated, allowing for a time window of assessment from 6 to 20 wks for those without a 12 wk measurement. Pts with progression before the 12 wk assessment were assigned a 100% increase. The average reduction in tumor burden (ARTB) was calculated as difference in waterfall AUC divided by the number of pts. ARTB captures the average percentage reduction in tumor measurements at 12 wks for a patient entering the trial. Results: Waterfall plot analysis demonstrated some tumor growth at 12 wks in 23.7% (IFL), 15.8% (FOLFOX), and 26.9% (IROX) of pts. In contrast, tumor shrinkage was observed in 67.9% (IFL), 71.6% (FOLFOX), and 61.4% (IROX) of pts. Total differential AUC was -34.4 (IFL), -61.6 (FOLFOX), and -30.4 (IROX) resulting in an ARTB of 16.0% (95% Confidence Interval (CI) (23.7%, 8.2%)) for IFL, 28.7% (35.1%, 22.2%) for FOLFOX, and 14.9% (22.5%, 7.3%) for IROX. Conclusions: Waterfall plot analyses are feasible in this and likely other CRC trials using conventional chemotherapy. Our analysis confirms the published results of N9741, but suggests a larger degree of benefit for individuals based on anti-tumor activity than captured by conventional response analysis. Waterfall plots provide a potentially useful new efficacy metric, the average reduction of tumor burden per pt, which should be validated in future trials. No significant financial relationships to disclose.

4036 Background: While BV prolongs OS when used with standard 1st- or 2nd-line chemotherapy (CT) in mCRC, no data exist on the effects of BBP. A previous report from BRiTE showed favorable median OS (27.1 mo, 95% CI 24.8-NE), with 1st line PFS (median 10.1 mo, 95% CI:9.7–10.4) comparable to historical mCRC trials, suggesting significant impact of post-progression survival on OS. This exploratory analysis evaluates the association of various pre- and post-treatment variables with OS in BRiTE. Methods: Pt population and methods have been described previously (Kozloff, ASCO 2006). All pts in BRiTE received BV as part of 1st-line therapy. The use of BBP and choice of CT were at investigator’s discretion. Kaplan-Meier methods were used to estimate PFS and OS. Cox’s proportional hazard model was used to assess the independent effects of pre- and post-treatment pt- related factors on OS, including age, ECOG PS, albumin, alkaline phosphatase, site of primary tumor, 1st-line CT regimen, 1st-line PFS, exposure to all 3 active CT agents, receipt of any 2nd-line CT, exposure to cetuximab, and BBP. Though there was variability observed in patterns of BBP, including continuous and discontinuous use, for the purpose of this analysis, BBP was defined as any exposure to BV after 1st progression (PD). Results: A total of 1,953 pts were treated in BRiTE. At median follow-up of 17.5 mo, there were 1,369 1st PD and 839 deaths. Among pts with 1st PD, 65.2% received any 2nd-line CT, 34.8% received cetuximab, and 53.8% received BBP. In a multivariate analysis, BBP and exposure to any 2nd-line CT were independently associated with increased OS (both p<0.0001). Age ≥65, PS ≥1, low albumin, elevated alkaline phosphatase, colon primary, and use of IFL were associated with inferior OS. Conclusions: BBP appears to be associated with longer OS in BRiTE. This finding supports the evaluation of BBP in prospective randomized clinical trials. Other factors that may have impacted this finding, including physician-related variables, will be investigated in future analyses. [Table: see text]

4020 Background: Adjuvant chemotherapy (AC) presents a substantial patient education challenge to medical oncologists (MOs). Findings from our 2005 pilot survey suggest that a significant fraction of colorectal cancer (CRC) survivors are willing to undergo AC for modest treatment benefits, but their understanding of risks and benefits may be suboptimal. This project attempted to validate these findings by surveying patients with CRC (Pts) who previously received AC. Methods: 150 Pts who received AC for CRC in the last 5 years were recruited to listen to an audio program on AC featuring interviews with clinical investigators (CIs) and Pts who received AC. Based on this input, Pts were asked whether they would undergo the same AC again for varying absolute treatment benefits. A corresponding survey asked 24 CRC CIs and 150 MOs to predict how patients would respond. The survey also queried Pts about their expectations of and experiences with AC side effects. Results: About 1/3 of Pts would be treated again with AC for a 1% absolute reduction in recurrence risk (ARRR), and about 2/3 believed a 5% ARRR would justify treatment. There were no statistically significant differences between responses of males and females or between Pts receiving oxaliplatin (OX) and those receiving other regimens. ( Table 1 ) The corresponding estimates of CIs and MOs were lower. Additionally, AC side effects were different than expected: 57% and 66% of Pts experienced less GI toxicity and alopecia, respectively, while 38% and 46% of Pts receiving OX experienced greater cold intolerance and numbness. Conclusions: Many potential obstacles exist in communicating with Pts about AC including heterogeneity in Pts’ attitudes towards risk/benefit trade-offs and preconceptions about treatment side effects. The next step in this initiative will be to examine these issues prospectively by evaluating the impact of an audio/web education supplement on the decision-making process. [Table: see text] No significant financial relationships to disclose.

11586 Background: Hand-foot skin reaction (HFSR) is the most common regorafenib adverse event. However, no intervention has demonstrated efficacy in preventing or palliating this adverse event, short of modulating the regorafenib dose. Methods: The Regorafenib Dose Optimization Study (ReDOS) was a randomized trial ( https://clinicaltrials.gov/ct2/show/NCT02368886 ); here we describe an a priori secondary analysis of ReDOS with the goal of assessing whether clobetasol 0.05% cream (a potent corticosteroid) applied to the palms and soles twice per day is more effective when prescribed pre-emptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the 1st 2 cycles of regorafenib. Results: Among 116 evaluable patients, 61 received pre-emptive clobetasol, and 55 reactive clobetasol. Baseline demographics were comparable between groups. During the 1st regorafenib cycle, 46% and 52% of patients developed HFSR with pre-emptive and reactive clobetasol, respectively (p = 0.52). However, during the 2nd cycle, 56% (of 47 total patients) and 80% (of 41 total patients), developed this toxicity with pre-emptive and reactive clobetasol, respectively (p = 0.02). Of note, during the 2nd cycle, rates of grade 1,2, and 3 HFSR were 40%, 11%, and 4% (pre-emptive) and 45%, 25%, and 10% (reactive) (p = 0.07). A sensitivity analysis to examine rates of no HFSR over all 2 regorafenib cycles showed that no HFSR occurred in 33% (of 61 total patients) with pre-emptive clobetasol versus 15% (of 55 total patients) with reactive clobetasol (p = 0.02). Patient-reported outcomes showed HFSR compromised activities of daily living, including getting dressed, preparing meals, walking, and even driving, with seemingly worse descriptive outcomes in patients who received reactive therapy. No adverse events from clobetasol were reported. Conclusions: Compared to reactive therapy, pre-emptive topical clobetasol might lessen regorafenib-induced HFSR. Clinical trial information: NCT02368886.