Grothey, Axel

11119 Background: Evaluation of prognostic factors in carcinoid tumors of the lung is limited due to the rarity of disease. This study assessed Ki-67 expression and other clinical variables as prognostic factors in 262 patients. Methods: A systematic search of Mayo Clinic lung cancer epidemiology and tumor registry databases from 1997 to 2009 identified 449 consecutive patients, with 262 having available tissue blocks [40 atypical carcinoids (AC) and 222 typical carcinoids (TC)]. Clinical data were collected by chart review. Tissue blocks were reviewed by 1/3 pathologists using WHO criteria. Tumors were tested for the Ki-67 index using digital image analysis (tumor tracing) by two operators. The association and predictive value of the factors with recurrence-free and overall survival (RFS and OS) were explored using univariable Cox proportional Hazards model and concordance (c) index. Results: Age, stage, smoking history, lymph node (LN) involvement and Ki-67 index were significant prognostic factors for RFS and OS. Median follow-up on alive-patients is 5 years (range: 0.006-5). Median percentage of Ki-67 index of AC and TC were 1.61% and 0.56% (P<0.0001), respectively. Patients with Ki-67 ≥ 1% had significantly worse RFS (HR=3.69, P<0.0001) and OS (HR=3.69, P=0.0007) compared with Ki-67 < 1% group. The c-index of Ki-67 (0.65) was comparable to the pathologic distinction between AC and TC (0.62 for original diagnosis and 0.63 for central-reviewed diagnosis). Conclusions: Ki-67 index cutoff value of 1% is a valuable prognostic biomarker for pulmonary carcinoids based on this large cohort. Our data also provide strong evidence for clinical variables such as age, stage, smoking history, and LN involvement as clinical prognostic factors in pulmonary carcinoids. A prognostic calculator incorporating Ki-67 and clinical variables is under development. [Table: see text]

3637 Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival and progression-free survival vs placebo (P) in patients with mCRC whose disease had progressed on other standard therapies. The most frequent grade 3 AEs were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash. We examined when these AEs first occurred and what impact they had on REG dosing. Methods: Adults with mCRC progressing after all standard therapies were randomized to receive REG 160 mg (n=505) or P (n=255) orally once daily for the first 3 weeks of each 4-week cycle. AEs were managed with dose modifications (reduction and interruption) according to the protocol. Results: The safety population comprised 753 pts (REG n=500, P n=253). The mean ± SD treatment duration was 12.1 ± 9.7 weeks for REG and 7.8 ± 5.2 weeks for P. Treatment-emergent AEs occurred in 99.6% of REG pts and 96.8% of P pts. AEs occurring in ≥10% more REG than P pts were fatigue, HFSR, anorexia, diarrhea, weight loss, voice changes, hypertension, rash/desquamation, oral mucositis, fever, hyperbilirubinemia, and low platelet count. The incidence of grade ≥3 HFSR, fatigue, hypertension, and rash/desquamation typically peaked in cycle 1 and tapered to a relatively stable lower incidence over later cycles, while the incidence of diarrhea remained relatively constant throughout the study; median time to first occurrence and worst grade of these AEs is shown in the table. AEs led to dose modifications in 66.6% of REG pts and 22.5% of P pts. Conclusions: The most common AEs in the REG group typically occurred early during treatment. Close early monitoring of AEs and proper management by dose modification is recommended. Clinical trial information: NCT01103323. [Table: see text]

3618 Background: Current prognostic tools and staging systems in CC use relatively few patient (pt) characteristics; including additional covariates may improve prediction. Using the large ACCENT database, we constructed clinically based NGs for OS and TTR in stage III CC that better separate pts into risk groups compared to AJCC v7 staging. Methods: 15,936 stage III pts accrued to phase III clinical trials since 1989 were used to construct Cox models for TTR and OS. Variables included age, sex, race, BMI, performance status, tumor grade, tumor stage, ratio of positive lymph nodes to nodes examined, number/location of primary tumors (any multiple versus single left, right, or transverse), and treatment (5FU variations vs. 5FU with oxaliplatin or irinotecan). Missing data (<18%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions included if p < 0.001. Final models were internally validated via bootstrapping for corrected calibration and C-indices for survival data. NG-defined risk tertiles were compared to AJCC v7 stage III for observed 3-year (yr) TTR and 5-yr OS for a subset of 7400 pts with complete data. Results: All variables were statistically and clinically significant for OS; age and race did not predict TTR. No meaningful interactions existed. NGs for OS and TTR were well calibrated and associated with C-indices of 0.66 and 0.65, respectively, vs. 0.58 and 0.59 for AJCC. NG risk tertiles were better separated than AJCC groups, (3-yr TTR, 5-yr OS below), with fewer mid-risk NG pts. Removing treatment from NGs did not affect performance (C=0.66 for OS and 0.65 for TTR). Conclusions: The proposed ACCENT NGs are internally valid and have the potential to aid prognostication, decision-making, and patient/physician communication in pts with stage III CC. [Table: see text]

3501 Background: Cumulative neurotoxicity commonly leads to early discontinuation of oxaliplatin-based therapy. In a relatively small, prematurely-discontinued, randomized study, IV CaMg was associated with reduced oxaliplatin-induced sNT (Grothey, JCO, 2011). N08CB was designed to definitively test whether IV CaMg significantly decreases cumulative oxaliplatin-related sNT. Methods: 353 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to 3 arms: IV CaMg (1g calcium gluconate, 1g magnesium sulfate) before and after oxaliplatin vs PL before and after vs CaMg before and PL after. The primary endpoint was cumulative sNT repeatedly measured by the sensory subscale of the EORTC QLQ-CIPN20. Secondary endpoints, using CTCAE 4.0 and an oxaliplatin specific neurotoxicity scale, were also assessed. Acute neuropathy data were also collected for 5 days following each oxaliplatin dose. The area under the curve (AUC) of the sensory subscale during the treatment cycles was used as summary measures for comparison. The Wilcoxon rank-sum tests were conducted for each treatment versus placebo arm, at 2.5%, adjusting for multiplicity using Bonferroni’s approach. Results: CaMg did not reduce cumulative sNT. Primary and secondary analyses data are summarized in the Table. In addition, there were no significant differences between arms regarding oxaliplatin administered doses or chemotherapy discontinuation rates. Also, there were no substantial differences in acute neuropathy scores or side-effects between study arms. Conclusions: This study does not demonstrate any activity of IV CaMg as a neuroprotectant against oxaliplatin-induced neurotoxicity. Clinical trial information: NCT01099449. [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]

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]